Introduction

The World Health Organization estimate that harmful alcohol consumption is the seventh leading cause of global death and disability [1]. Alcohol causes a wide spectrum of pathology, but alcohol-related liver disease (ALD) causes a significant proportion of the attributable morbidity and mortality [1]. This proportion varies geographically and is generally highest in middle-aged males. In some areas, such as the United Kingdom, almost 90% of alcohol-related deaths are caused by ALD (Fig. 1) [1, 2].

Figure 1

The relative proportion of alcohol-related deaths attributed to different pathologies as recorded by ICD-10 code classification for the United Kingdom in 2016. Liver disease accounts for almost 90% of alcohol-related deaths (analysis of data from the archives of the Office of National Statistics, Ryan Buchanan [2])

Until the 1970s the association between alcohol and liver cirrhosis had been noted, but doubt about a causal relationship persisted. Uncertainty gained traction because not all people with alcohol use disorder (AUD) developed cirrhosis, but it was often observed when malnutrition was also present. This led to debate concerning whether it was malnutrition rather than alcohol that was the primary risk factor for liver cirrhosis. However, a team working in New York settled the argument. Leiber et al. fed ethanol to 15 baboons as part of an otherwise balanced nutritious diet. The team observed the whole spectrum of alcohol-related liver disease (ALD) and glimpsed the underlying pathogenic pathway [3].

Since the 1970s, alcohol has become more available and the incidence of ALD has increased. This review summarizes the latest epidemiology of ALD and gives an overview of the spectrum of attributable liver pathology. It also synthesizes the evidence for best practice in clinical hepatology and addiction psychiatry to understand and manage this complex comorbid condition.

Epidemiology of alcohol-related liver disease

In 2017 liver disease caused more than 1.32 million deaths world-wide. In Europe, North and South America and Central Asia the most common cause of liver cirrhosis is ALD [4]. Countries in the European region consume some of the highest quantities of alcohol [5], with more than 2 million years of life lost to liver disease in people under the age of 50 years, with 60–80% of these attributed to alcohol [6]. In some European countries, notably Finland and the United Kingdom, there has been an increase in ALD-related deaths in recent decades which has been associated with a reduction in the relative price of alcohol and a steep rise in consumption [2, 6].

An overall increase in alcohol consumption has been noted world-wide [5, 7], including in the United States [8], where there has been a significant rise in the prevalence of harmful consumption of alcohol [9], and a corresponding 65% increase in annual liver cirrhosis mortality since 2009. Notably, this increased mortality can be attributed almost entirely to ALD in young people [8].

At an individual level the probability of developing ALD has a close and exponential relationship with levels of alcohol consumption [10-12]. However, risks of ALD are increased with only modestly elevated levels of consumption [12]. ALD has also been associated with a number of genetic polymorphisms [13], and is more likely in people with comorbid obesity or chronic viral hepatitis [14, 15]. Social deprivation is also a significant risk factor, with individuals in the two lowest quintiles of the Index of Multiple Deprivation, and particularly those who are homeless are at greatest risk of liver morbidity and mortality [16-19]. This is thought to be a consequence of the increased affordability of alcohol [6] and the high prevalence of multiple-risk comorbidities in these populations, including hepatitis C, smoking, obesity and a lack of exercise [16]. The combination of alcohol with a range of other factors which cause harm to health may account for the so-called ‘alcohol harm paradox’, where deprived individuals drinking the same quantities of alcohol as more affluent individuals are disproportionately affected with ALD [16].

The spectrum of alcohol-related liver disease

Excessive consumption of alcohol leads to a spectrum of liver disease, including liver steatosis, fibrosis, compensated cirrhosis (CC), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and alcoholic hepatitis (AH) (see Fig. 2). A ‘fatty liver’ or steatosis is an extremely common finding in people who drink alcohol, and the accumulation of fat in the liver can occur after just a few days of drinking alcohol. The rate of progression of liver disease varies in different subpopulations, but is increased at all stages (steatosis to fibrosis through to DC and HCC) by the consumption of alcohol. Conversely, the rate of progression is reduced by abstinence [20]. AH is a distinct acute disease of the liver that usually occurs in people with AUD who have recently consumed large quantities of alcohol. It typically, but not exclusively, occurs in people with underlying liver cirrhosis (see Fig. 2) [21].

Figure 2

An overview of the spectrum of alcohol-related liver disease. Images courtesy of Dr M. Isabel Fiel (Fig. 1 from Crabb et al. [36], reproduced with permission from John Wiley and Sons). [Colour figure can be viewed at wileyonlinelibrary.com]

Overview of hepatic metabolism of alcohol

Hepatocytes make up 70% of the liver mass and play the central role in alcohol metabolism. Within each cell there are three enzymic pathways for the metabolism of alcohol. The major pathway occurs in the cytoplasm of the hepatocytes. In this pathway ingested alcohol is oxidized by alcohol dehydrogenase to acetaldehyde. In a second pathway—the major inducible pathway—alcohol is oxidized to acetaldehyde in the smooth endoplasmic reticulum by the cytochrome p450 2EI enzyme. In the third, more minor inducible pathway, alcohol is metabolized to acetaldehyde via a catalase enzyme. The acetaldehyde produced by all three pathways is toxic to the cell, so it is rapidly transported to the mitochondria where it is converted to acetate via an acetaldehyde dehydrogenase enzyme. The acetate then passes into the circulation to play a role in metabolism elsewhere.

How does alcohol damage the liver?

The mechanisms by which alcohol directly harms the liver sufficiently to cause chronic liver disease are complex. Excessive alcohol consumption increases the production of enzymes necessary for its metabolism. This leads to increased levels of acetaldehyde and harmful pro-oxidants, which are directly cytotoxic to hepatocytes. As a natural response to tissue injury, fibrogenesis occurs to isolate and limit damage to a specific area of tissue. Fibrogenesis occurs because the liver injury activates hepatic stellate cells, which form extracellular matrix proteins and release inflammatory proteins that lead to a cycle of further activation, protein deposition and fibrogenesis. Cirrhosis is an advanced form of fibrosis where the normal liver micro- and macro-structure has been lost and is characterized by the development of regenerative nodules divided by fibrous septa. Liver cirrhosis is considered to be a pre-malignant condition. The processes leading to liver cirrhosis including tissue injury and repair, alongside directly mutagenic properties of the acetaldehyde and harmful pro-oxidants, create an environment prone to develop HCC.

The underlying causes of AH and the intense inflammatory infiltration of the liver that characterizes the condition are not completely understood. It is probable that a complex interplay of factors is involved. There is evidence that alcohol increases gut permeability, which leads to high levels of bacterial toxins (e.g. lipopolysaccharide endotoxin) passing from the gut into the circulation. In AH it is postulated that these activate inflammatory responses within the liver. Additionally, alcohol directly activates innate liver immune cells (called Küpffer cells) and sensitizes hepatocytes to some of the inflammatory proteins they produce leading to cell death. Hepatocyte death itself activates the inflammatory cascade, leading to further cell death, and in this way the pathogenesis of AH is sustained.

Liver fibrosis and cirrhosis

Clinical manifestations

Opportunities to screen for liver disease in patients with harmful alcohol consumption are often missed, and many patients only present to health services once symptoms relating to DC have occurred [22, 23]. As indicated in Fig. 2, cirrhosis can progress from CC to DC at a rate of 5–7% per year [24]. As well as alcohol consumption, a range of factors, including infection, medications such as benzodiazepines, surgical operations such as heart valve replacements and gastrointestinal bleeding can trigger progression to DC. DC is characterized by the development of ascites (free fluid within the abdominal cavity), abnormal clotting, jaundice (yellow discolouration of the skin and sclera) and encephalopathy (resulting in confusion, drowsiness and coma).

Assessment

As alcohol-related liver fibrosis and CC develops silently over many years, the challenge is to make an early initial diagnosis. Accordingly, numerous targeted screening approaches have been developed in people who drink alcohol at high levels to try to identify disease at an earlier stage. According to European guidelines, targeted screening is appropriate in men drinking >30 g/day and women drinking >20 g/day of ethanol, but should also be considered in those presenting with other physical manifestations of AUD, such as cardiomyopathy and peripheral neuropathy [25].

Standard liver function tests including raised blood levels of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase are poor markers of ALD, and should only be considered in conjunction with a specific test for liver fibrogenesis [26]. A range of biochemical fibrosis markers are recommended for this assessment, including the enhanced liver fibrosis (ELF) test, fibrosis 4 (Fib4) test and FibroTest [25]. However, in the United Kingdom the current clinical guidelines on the management of cirrhosis recommend that patients with AUD be referred directly for transient elastography (TE) [27]. In TE a shear wave is transmitted through the liver and this gives a measure of liver stiffness in kilopascals (kpa). Liver stiffness correlates with the degree of liver fibrosis, and TE is therefore a useful non-invasive assessment for liver cirrhosis and advanced fibrosis [28]. In cases of diagnostic uncertainty, or to more accurately stage the degree of liver fibrosis, a liver biopsy is still appropriate in some cases. However, the additional diagnostic and prognostic information from a liver biopsy needs to be weighed against potential serious complications which occur following <2% of procedures [25, 27]. Patients with DC usually present to health-care services with acute illness, and the diagnosis is apparent from clinical examination of the patient for hepatic encephalopathy, ascites and jaundice.

Treatment

There are no licensed pharmacological treatments to reverse ALD. Management is therefore focused upon monitoring for complications of cirrhosis, abstinence and other life-style modifications, such as weight loss and dietary modification—there is observational evidence that coffee reduces progression to cirrhosis [29]. For a small minority of patients with end-stage disease, liver transplantation (LT) may be required.

Patients with established liver cirrhosis should be monitored with ultrasonography for the development of HCC and with regular blood tests to assess their degree of liver function, including the ability to synthesize proteins that are essential for the normal functioning of the body. Consideration should also be given to a screening endoscopic examination for oesophageal varices (swollen veins in the oesophagus, due to congestion of the portal vein), which are at risk of rupture.

Abstinence from alcohol is key to preventing disease progression in patients with liver fibrosis and CC [30]. Indeed, even at an advanced stage, inflammation and fibrosis remain reversible on cessation of a, and liver steatosis is considered to be fully reversible with appropriate life-style modifications [20]. Since the 1960s it has been observed that abstinence from alcohol is also key for preventing death in patients with decompensated ALD [31]. This is supported by recent prospective [32] and retrospective cohort studies [33].

All interventions for alcohol use disorders are underpinned by a psychosocial framework [34]. Although the evidence base for psychosocial treatment in patients in ALD is limited [30], a systematic review of treatment trials in ALD found that integrating specialist AUD treatment within hepatology services resulted in higher abstinent rates than referral to a separate treatment service [35]. Recent international ALD treatment guidance now recommends that to engage patients in harm reduction, or ideally achieve abstinence, appropriate psychosocial support services should be available within hepatology centres as part of an integrated multidisciplinary team [25, 36].

Pharmacological treatment in patients with moderate to severe alcohol dependence may also be required for medically assisted alcohol withdrawal, or relapse prevention, especially given the many years of untreated AUD prior to presentation, and the need for long-term sustained abstinence. In terms of alcohol withdrawal, standard practice is variable but there is good evidence for the efficacy of benzodiazepines and carbamazepine for medically assisted withdrawal from alcohol, and preventing further complications such as delirium and seizures [34]. For patients with decompensated liver cirrhosis, and impaired synthetic function, carbamazepine is not recommended and doses of benzodiazepine medication should be reduced, with frequent objective monitoring of symptoms [37]. In clinical practice, oxazepam or lorazepam, which have reduced hepatic metabolism are sometimes used [37]. Given the poor nutritional status of many patients with ARLD, a high index of suspicion needs to be maintained for the development of Wernicke–Korsakoff syndrome and all patients in alcohol withdrawal should be treated with parenteral thiamine (usually in combination with other B vitamins) for 3–5 days until no symptoms (confusion, ataxia, opthalmoplegia) remain or treatment continued until no further improvement in symptoms found [34].

Relapse prevention medication may also be considered (Table 1). Acamprosate, naltrexone, nalmefene and disulfiram are all approved in one or more region for the treatment of alcohol dependence [38]. Baclofen has been recently approved for AUD treatment in France only for patients who have not responded to other treatments [39].

Table 1. Relapse prevention medications in patients with AUD and ALD (adapted from AASLD [36].

Disulfiram inhibits the enzyme acetaldehyde dehydrogenase, causing accumulation of acetaldehyde following alcohol consumption, which can have potentially severe adverse effects and so should be used with caution, and only after a thorough assessment in patients with ALD [34]. There are also concerns about potential hepatotoxic effects of naltrexone [36] with five to 10-fold increases in naltrexone plasma concentrations reported in patients with cirrhosis [38, 40]. However, data suggest that high doses (up to 300 mg daily), concurrent use of non-steroidal analgesics and obesity may account for the raised transaminases seen in early studies, and Phase 2 studies showed no evidence of toxicity at doses of 800 mg daily for 1 week. Nalmefene, another opioid system modulator, structurally similar to naltrexone, is extensively metabolized by the liver, largely by glucuronidation, and has not been identified to have a risk of hepatotoxicity, although one small study of patients with liver disease showed significantly reduced clearance of nalmefene inversely proportional to the level of hepatic pathology. Its efficacy has not been specifically investigated in patients with ALD [38].

Acamprosate is derived from homotaurine, a non-specific gamma aminobutyric acid (GABA) agonist and calcium. It is not metabolized by the liver and has no impact on drugs subject to hepatic metabolism or which have an impact upon the CP450 system. It is excreted via the kidneys, although there are no trials specifically assessing its effects in patients with ALD, Acamprosate should be considered as a treatment option in this patient group [38]. Only baclofen, a GABA-B receptor agonist, has been assessed in patients with established cirrhosis. In a single randomized controlled trial (RCT), patients who received baclofen were twice as likely to report abstinence than patients receiving placebo and no hepatotoxic effects were recorded [41]. Importantly, this study demonstrated the safety of baclofen in patients with DC. Conversely, a later RCT showed no benefit from baclofen compared to placebo. However, this trial was conducted in an exclusively male, relatively elderly cohort with hepatitis C and the studies used different outcomes measures, so direct comparison is difficult [42]. In recognition of this uncertainty, but mindful that it is the only relapse prevention medication to be trialled in patients with cirrhosis, an international consensus statement published in 2018 recommended consideration of baclofen to treat AUD in patients with ‘advanced liver disease’ (see Table 1), and this has been supported by recent US guidance [36, 43].

Liver transplantation

Abstinent patients with end-stage ALD or those with a range of extrahepatic manifestations can be considered for LT. ALD is increasingly an indication for LT in the United States [44] and Europe [45]. Since the late 1980s ALD has been considered an appropriate indication for LT, and although early survival rates were poor [46], 5-year post-transplant survival in patients with ALD is now comparable to patients transplanted for other indications and the 1-year post-transplant survival is greater than 80% [44]. However, patients with ALD are at risk from multisystem effects of alcohol including, cardiomyopathy, pancreatitis, dementia and malnutrition, and therefore pre-operative assessment needs to be rigorous [47]. Malnutrition is particularly common in patients with ALD [48] and is associated with worse outcomes [49].

Abstinence from alcohol is a prerequisite before a patient is considered for LT, and in many countries a strict 6-month period of abstinence is enforced; however, there is a lack of data supporting such a stringent approach and it is not endorsed by international guidelines. Nevertheless, a careful assessment of risk of relapse is essential. This should involve a multidisciplinary team and include careful exploration of risk factors for relapse, such as a family history of AUD, previous unsuccessful attempts at abstinence and poor social support networks [50, 51].

Prognosis

Patients with CC have a 1-year survival of more than 90% [24]. The likelihood of complications and death in patients with DC correlates closely with scoring systems such as the Child–Turcott–Pugh score or the model for end-stage liver disease score [36]. The Child–Turcott–Pugh score places patients into three classes on the basis of the presence or absence of encephalopathy, jaundice, ascites or coagulopathy [52]. In a systematic review of more than 118 cohort studies, those with the most severe decompensated disease (class C) had a 1-year survival of less than 50% [24].

Hepatocellular carcinoma

Clinical manifestations

ALD is the most common cause of HCC in Europe and North America and accounts for 30% of cases world-wide [53]. For an individual with CC the annual probability of developing HCC is 2.9–5.6% per year, but the incidence is higher in individuals with DC (Fig. 2) [54].

In patients with known ALD, unexplained progression from CC to DC should lead to investigation for a possible HCC. Otherwise, tumour-specific symptoms, including right upper quadrant fullness, weight loss, anorexia or early satiety, are often vague and easily dismissed. Consequently, HCC is often identified during routine surveillance imaging in patients with ALD, or as an incidental finding in patients who have received imaging of their liver for an unrelated indication.

Despite international guidance advocating 6-monthly ultrasound imaging of the liver for patients with ALD, a significant proportion of cases present in patients who have not been effectively engaged with surveillance imaging programmes [54]. Accordingly, patients with ALD present with more advanced cancer and have worse outcomes than patients with HCC due to another underlying cause [55].

Assessment

In patients with established cirrhosis, computerized tomography (CT) or magnetic resonance imaging (MRI) imaging may be sufficient to establish the diagnosis if pathognomonic features are present. In patients without established cirrhosis or in cases where there is diagnostic uncertainty a biopsy for histology may be necessary, although interval imaging to assess changes in lesion size or character over a short time-period may sometimes be appropriate [56]. The investigation of liver lesions should always be directed by a cancer multidisciplinary service [56].

Treatment

The treatment of HCC in patients with ALD is complex and evolving. In the first instance it is important to establish whether the goal of therapy is palliative or curative. To determine which approach should be taken, a number of patient and tumour-related factors need to be considered. These include whether the patient has CC or DC; whether they would be considered a candidate for LT (i.e. are abstinent from alcohol); and tumour size, number and location within the liver.

Where potentially curative approaches are considered appropriate these may include radio-frequency ablation of the tumour, resection of the tumour or LT. Potential palliative approaches include trans-arterial chemo-embolization, systemic chemotherapy or best supportive care [56].

Prognosis

Prognosis of HCC varies depending on the treatment modality that can be offered. Patients with a small single tumour that is resected have a 5-year survival of 80–90%. In patients who successfully undergo LT, median 5-year survival is as high as 70%; however, where curative therapy cannot be offered, 5-year survival is considerably lower, with those in a terminal stage of disease surviving just a few months [56].

Alcoholic hepatitis (AH)

AH was first clinically defined in 1961 by clinicians working at the Royal Free Hospital in London [57]. It is a distinct clinical syndrome from DC and can occur in patients without established liver cirrhosis [21]. Patients typically present to medical services with jaundice following a recent escalation in alcohol consumption. Serum biochemistry tests show an elevated bilirubin but usually only a modest elevation in ALT. The liver is often enlarged and tender and the patient may complain of nausea, fevers and sometimes vomiting. Histology shows a characteristic inflammatory cell infiltrate alongside other distinctive features.

Assessment

History, examination and blood tests are an important part of the initial assessment to establish the level and duration of alcohol consumption and the clinical and biochemical features of AH. Liver biopsy is not an essential part of the diagnostic pathway but should be undertaken if there is diagnostic uncertainty. Imaging of the liver, usually via ultrasonography, is important to exclude other causes of jaundice and in the presence of fever clinicians should actively exclude infection.

Treatment

To achieve a positive outcome, it is essential that patients diagnosed with AH become completely abstinent. Most cases will be managed in hospital, where they can be monitored for complications and, in severe cases, consideration given to the provision of specific interventions.

In severe cases, corticosteroids are marginally beneficial for short-term survival but convey risks of infection and variceal bleeding, so should only be continued in patients who show a positive initial response [58]. A single trial showed a significant reduction in 1-month mortality by adding a 5-day infusion of N-acetylcysteine to prednisolone, although the reduction in mortality was non-significant in the longer term [59]. Oral or nasogastric tube feeding is also important. Poor nutrition is associated with adverse outcomes in AH [60], and nasogastric feeding has been shown to be comparable to corticosteroid therapy in a single randomized control trial [61], although a later study which combined nasogastric feeding and corticosteroid therapy was not found to be superior to corticosteroid therapy alone [60].

Prognosis

Even with treatment, severe alcoholic hepatitis has a high mortality. In a large UK-based four-arm RCT 28-day mortality rate ranged from 14 - 18%, and 58% of the cohort had died at 12 months [58]. A Spanish study of 142 patients with biopsy-proven AH has shown that abstinence from alcohol was the only factor significantly associated with long-term survival [62].

New developments in treatment of AH

In the absence of any treatment for AH that significantly improves long-term outcomes, trials focusing on hepatic (but not alcohol) treatment are ongoing [63]. LT is now being used in some countries as a therapeutic strategy for selected patients with AH. In 2011 a highly selected case series in France assessed outcomes for patients with AH receiving a liver transplant [64]. The study showed a significant survival benefit compared to matched controls in selected patients with severe alcoholic hepatitis and comparable survival outcomes to patients receiving LTs for other indications. Additionally, subsequent studies have shown that patients receiving a transplant for AH were no more likely to return to drinking than those receiving a transplant after a period of abstinence from alcohol [60]. However, although transplantation for AH now occurs in the United States and parts of Europe it has not become practice in the United Kingdom [65]. Indeed, a recent UK trial investigating the utility of LT in patients with AH failed to recruit any participants [65].

Conclusion

Despite overwhelming evidence of the high levels of morbidity and mortality due to liver disease in patients with AUD, and alcohol-related deaths in patients with liver disease, research and clinical practice aimed at developing a robust evidence base to improve outcomes in this comorbid group remains in its infancy. The paucity of evidence for integrated alcohol treatment in ALD is particularly surprising, given that abstinence improves outcomes at all stages of liver disease, and the evidence base for psychosocial and pharmacological treatment for patients with AUD is well established.

The re-purposing of the drug baclofen has shown some promise in developing collaborations to explore treatments in this comorbid group, but greater integration of both psychosocial and pharmacological treatment pathways across hepatology and addictions is needed before real progress will be made.

Summary

Alcohol-related liver disease (ALD) constitutes a significant global health problem, representing a leading cause of mortality and morbidity, particularly among middle-aged males. While the link between alcohol consumption and liver cirrhosis has been recognized for decades, the causal relationship was initially debated due to the influence of confounding factors such as malnutrition. However, subsequent research definitively established alcohol as a primary risk factor. Increased alcohol availability has led to a rise in ALD incidence, necessitating a comprehensive understanding of its epidemiology, pathology, and management.

Epidemiology of Alcohol-Related Liver Disease

ALD is a prevalent cause of liver cirrhosis globally, particularly in regions with high alcohol consumption rates, such as Europe and parts of North America. Significant increases in ALD-related mortality have been observed in certain European countries, correlated with decreased alcohol prices and increased consumption. Globally, rising alcohol consumption is associated with increased ALD prevalence, notably in the United States, where a substantial increase in liver cirrhosis mortality has been attributed almost entirely to ALD among young people. The risk of developing ALD exhibits a strong, exponential relationship with alcohol consumption levels; however, even moderately elevated consumption increases risk. Genetic predispositions and comorbidities such as obesity and chronic viral hepatitis further elevate risk. Social deprivation represents another significant risk factor, linked to increased alcohol affordability and a higher prevalence of comorbidities within these populations. This contributes to the "alcohol harm paradox," whereby deprived individuals experience disproportionately higher ALD rates despite consuming similar alcohol quantities as more affluent individuals.

The Spectrum of Alcohol-Related Liver Disease

Excessive alcohol consumption results in a spectrum of liver diseases, ranging from steatosis (fatty liver) and fibrosis to compensated and decompensated cirrhosis, hepatocellular carcinoma (HCC), and alcoholic hepatitis (AH). Steatosis is common, developing after only minimal alcohol consumption. Disease progression varies across populations but is accelerated at all stages by continued alcohol use and slowed by abstinence. AH is a distinct acute liver disease usually occurring in individuals with alcohol use disorder (AUD) who have recently consumed large quantities of alcohol, often in those with underlying liver cirrhosis.

Overview of Hepatic Metabolism of Alcohol

Hepatocytes, comprising the majority of liver mass, are central to alcohol metabolism. Three enzymatic pathways metabolize alcohol within hepatocytes: alcohol dehydrogenase in the cytoplasm, cytochrome p450 2EI in the smooth endoplasmic reticulum, and catalase. The resulting acetaldehyde, a cytotoxic substance, is rapidly converted to acetate in the mitochondria, which subsequently enters the circulation.

How Does Alcohol Damage the Liver?

The mechanisms of alcohol-induced liver damage are intricate. Excessive alcohol consumption boosts the production of metabolic enzymes, leading to increased levels of acetaldehyde and harmful pro-oxidants, directly damaging hepatocytes. This injury triggers fibrogenesis—the formation of scar tissue—as the liver attempts to limit damage. Advanced fibrosis leads to cirrhosis, a pre-malignant condition. The processes involved in cirrhosis, coupled with the mutagenic properties of acetaldehyde and pro-oxidants, foster an environment conducive to HCC development. AH's pathogenesis likely involves increased gut permeability, leading to heightened levels of bacterial toxins that activate inflammatory responses within the liver. Alcohol also directly activates Kupffer cells (innate liver immune cells), promoting hepatocyte death and sustaining the inflammatory cascade.

Liver Fibrosis and Cirrhosis: Clinical Manifestations, Assessment, and Treatment

Liver fibrosis and cirrhosis often progress silently, with many individuals presenting only after symptoms of decompensated cirrhosis (DC) appear. Progression from compensated cirrhosis (CC) to DC can occur at a rate of 5–7% annually. Several factors besides alcohol consumption can trigger this progression. DC is characterized by ascites, abnormal clotting, jaundice, and encephalopathy. Early diagnosis is crucial due to the silent progression of ALD. Targeted screening is recommended for individuals with high alcohol consumption, along with consideration of other AUD physical manifestations. Standard liver function tests are insufficient, necessitating tests for liver fibrogenesis (e.g., ELF, Fib4, FibroTest, transient elastography [TE]). Liver biopsy remains an option for diagnostic uncertainty or staging. Treatment focuses on abstinence, lifestyle modifications, and supportive care; liver transplantation may be necessary in end-stage disease.

Hepatocellular Carcinoma: Clinical Manifestations, Assessment, and Treatment

ALD is a leading cause of HCC globally. The annual probability of HCC development in individuals with CC is significant, increasing further in those with DC. HCC often presents with vague symptoms, leading to late diagnosis. Surveillance imaging is recommended, but many cases still present with advanced disease. Diagnosis involves imaging (CT, MRI) and potentially biopsy. Treatment strategies depend on disease stage and patient factors, ranging from curative approaches (radiofrequency ablation, resection, LT) to palliative care (chemoembolization, systemic chemotherapy). Prognosis varies widely based on treatment options.

Alcoholic Hepatitis (AH): Clinical Manifestations, Assessment, and Treatment

AH, distinct from DC, can occur without cirrhosis. Patients typically present with jaundice and elevated bilirubin following increased alcohol consumption. Diagnosis involves clinical evaluation, blood tests, and potentially liver biopsy and imaging. Abstinence is essential for positive outcomes. Treatment in severe cases may include corticosteroids (with caveats regarding risks), N-acetylcysteine, and nutritional support.

Alcoholic Hepatitis (AH): Prognosis and New Developments in Treatment

Severe AH carries high mortality. Abstinence is the most crucial factor for long-term survival. Liver transplantation is being explored as a therapeutic option for selected patients in some regions, with promising outcomes in certain studies. However, the widespread adoption of LT for AH remains limited.

Conclusion

Despite the substantial morbidity and mortality associated with ALD, research and clinical practice lag in developing effective interventions. The limited evidence for integrated alcohol treatment in ALD is surprising given the benefits of abstinence at all stages. Further integration of psychosocial and pharmacological treatment across hepatology and addiction medicine is critical to improve outcomes for this comorbid population.

Summary

Alcohol-related liver disease (ALD) is a significant global health problem, responsible for a substantial portion of alcohol-attributable mortality and morbidity. While the link between alcohol and cirrhosis was recognized earlier, a definitive causal relationship was only established in the 1970s. Since then, increased alcohol availability has led to a rise in ALD cases worldwide. This review examines the epidemiology of ALD, its diverse pathological manifestations, and current best practices in its clinical management.

Epidemiology of Alcohol-Related Liver Disease

ALD is a leading cause of cirrhosis globally, particularly in Europe, the Americas, and Central Asia. High alcohol consumption rates in several European nations correlate with a high incidence of ALD-related deaths, often exacerbated by reduced alcohol prices and increased consumption. Globally, rising alcohol consumption, including in the United States, has resulted in a dramatic increase in ALD-related mortality, especially among younger individuals. The risk of developing ALD is strongly linked to alcohol consumption levels, with even moderate increases in consumption elevating risk. Genetic factors, obesity, chronic viral hepatitis, and social deprivation also contribute to ALD susceptibility. Deprived populations often face a disproportionate impact from alcohol consumption, potentially due to the combined effect of multiple health risks and increased alcohol affordability.

The Spectrum of Alcohol-Related Liver Disease

Excessive alcohol consumption causes a range of liver diseases, progressing from steatosis (fatty liver) to fibrosis, compensated and decompensated cirrhosis, hepatocellular carcinoma (HCC), and alcoholic hepatitis (AH). The progression rate varies, but alcohol consumption accelerates it at all stages, while abstinence slows it down. AH is a distinct acute liver disease typically occurring in individuals with alcohol use disorder (AUD) who have recently consumed substantial amounts of alcohol, often in the context of underlying cirrhosis.

Overview of Hepatic Metabolism of Alcohol

Hepatocytes are central to alcohol metabolism, employing three enzymatic pathways. The primary pathway involves alcohol dehydrogenase in the cytoplasm; a significant inducible pathway uses cytochrome p450 2EI in the smooth endoplasmic reticulum; and a minor inducible pathway utilizes catalase. Acetaldehyde, a toxic byproduct of these pathways, is converted to acetate in the mitochondria, then entering the circulation.

How Does Alcohol Damage the Liver?

The mechanisms of alcohol-induced liver damage are multifaceted. Increased alcohol metabolism leads to elevated acetaldehyde and pro-oxidants, directly damaging hepatocytes. This injury triggers fibrogenesis, a process of tissue repair that can progress to cirrhosis, a pre-malignant condition. The combination of tissue injury, repair, and acetaldehyde's mutagenic effects fosters an environment conducive to HCC development. In AH, increased gut permeability allows bacterial toxins to enter the circulation, activating liver inflammatory responses. Alcohol also directly activates Kupffer cells and sensitizes hepatocytes, further contributing to the inflammatory cascade and cell death.

Liver Fibrosis and Cirrhosis: Clinical Manifestations, Assessment, and Treatment

Liver fibrosis and cirrhosis often develop asymptomatically, with patients often presenting only after decompensated cirrhosis (DC) symptoms appear. Progression from compensated to decompensated cirrhosis can be rapid. DC is characterized by ascites, clotting abnormalities, jaundice, and encephalopathy. Early diagnosis is challenging, necessitating targeted screening in high-risk individuals. While standard liver function tests are limited, biochemical fibrosis markers and transient elastography (TE) provide more effective assessment tools. Liver biopsy remains an option for cases requiring further clarification or staging. No licensed treatments reverse ALD; management focuses on monitoring complications, abstinence, lifestyle modifications (weight loss, diet), and liver transplantation for end-stage disease. Abstinence is crucial for preventing disease progression and improving survival at all stages, even in advanced cirrhosis. Psychosocial support integrated within hepatology services improves abstinence rates.

Pharmacological interventions might include medically assisted withdrawal (benzodiazepines, carbamazepine, with modifications for patients with liver dysfunction), and relapse prevention medications (acamprosate, naltrexone, nalmefene, disulfiram, and baclofen). Considerations for specific medications should be made based on potential interactions with liver function and the patient’s specific needs.

Liver Transplantation

Liver transplantation is an option for abstinent patients with end-stage ALD or extrahepatic complications, offering comparable survival rates to those receiving transplants for other reasons. However, rigorous pre-operative assessment addressing issues like malnutrition is necessary. A six-month abstinence period is often required before transplantation, although evidence for this stringent requirement is lacking. A multidisciplinary assessment of relapse risk is essential.

Hepatocellular Carcinoma: Clinical Manifestations, Assessment, and Treatment

ALD is a major cause of HCC globally. HCC in ALD patients often presents late due to vague symptoms or is discovered incidentally during imaging. Regular surveillance imaging is recommended but often lacks adherence. Diagnosis is based on imaging (CT, MRI) and biopsy, with management dictated by a cancer multidisciplinary team. Treatment options range from curative approaches (radiofrequency ablation, resection, liver transplantation) to palliative measures (chemoembolization, systemic chemotherapy, supportive care). Prognosis varies widely depending on treatment modality and disease stage.

Alcoholic Hepatitis: Clinical Manifestations, Assessment, Treatment, and Prognosis

AH is a distinct clinical syndrome that can occur without cirrhosis. Patients present with jaundice, elevated bilirubin, and hepatic inflammation. Diagnosis relies on clinical presentation, blood tests, and, if needed, liver biopsy. Complete abstinence is crucial for positive outcomes. Treatment for severe AH may involve corticosteroids (with risks), and N-acetylcysteine, and nutritional support (oral or nasogastric feeding). Even with treatment, mortality remains high; abstinence is strongly linked to long-term survival. Liver transplantation is emerging as a therapeutic option in selected cases, although its use varies geographically.

Conclusion

Despite the significant morbidity and mortality associated with ALD, further research is needed to enhance treatment efficacy and improve patient outcomes. A better integration of alcohol treatment services into hepatology care is vital, as abstinence is a key determinant of positive outcomes at all stages of ALD, and established treatments for AUD can be effective. While some progress is being made with novel therapeutic approaches, a more collaborative and integrated approach between hepatology and addiction medicine is essential to effectively address this critical public health issue.

Summary

Alcohol-related liver disease (ALD) is a significant global health problem, accounting for a substantial portion of alcohol-related deaths and disabilities. While the link between alcohol and liver cirrhosis has been known for decades, the exact mechanisms and risk factors are complex and continue to be studied. This includes the role of genetics, nutritional status, and socioeconomic factors.

Epidemiology of Alcohol-Related Liver Disease

Worldwide, alcohol consumption is increasing, leading to a rise in ALD cases and mortality. Europe, North and South America, and Central Asia show particularly high rates of ALD-related cirrhosis. Increased alcohol affordability and consumption are correlated with rising ALD deaths in some European countries. Individual risk increases exponentially with alcohol consumption, but even moderate drinking elevates the risk. Genetic factors, obesity, viral hepatitis, and social deprivation also contribute significantly to ALD risk. The "alcohol harm paradox" highlights the disproportionate effect on deprived individuals, likely due to co-occurring health risks.

The Spectrum of Alcohol-Related Liver Disease

Excessive alcohol consumption causes a range of liver diseases, including fatty liver (steatosis), fibrosis, compensated and decompensated cirrhosis, hepatocellular carcinoma (HCC), and alcoholic hepatitis (AH). Steatosis is common, even after short periods of drinking. Disease progression is accelerated by continued alcohol use and slowed by abstinence. AH is a severe acute liver condition often seen in those with AUD and high recent alcohol intake, frequently alongside cirrhosis.

Overview of Hepatic Metabolism of Alcohol

Hepatocytes are central to alcohol metabolism, using three enzymatic pathways. The primary pathway, in the cytoplasm, uses alcohol dehydrogenase to convert alcohol to acetaldehyde. A secondary pathway, in the smooth endoplasmic reticulum, utilizes cytochrome p450 2EI. A minor pathway involves catalase. The toxic acetaldehyde is converted to acetate in the mitochondria, then entering circulation.

How Does Alcohol Damage the Liver?

Alcohol damages the liver through several mechanisms. Increased alcohol metabolism leads to higher acetaldehyde and pro-oxidant levels, directly harming hepatocytes. The liver's response to this injury is fibrogenesis, eventually leading to cirrhosis—a pre-malignant condition. The mutagenic properties of acetaldehyde and pro-oxidants contribute to HCC development. In AH, increased gut permeability and immune cell activation contribute to liver inflammation and cell death.

Liver Fibrosis and Cirrhosis

Clinical Manifestations

ALD often goes undetected until decompensated cirrhosis (DC) symptoms appear, including ascites, clotting abnormalities, jaundice, and encephalopathy. Progression from compensated cirrhosis (CC) to DC can be rapid.

Assessment

Early diagnosis is challenging because fibrosis and CC develop silently. Screening guidelines suggest testing individuals with high alcohol consumption, or those with other AUD symptoms. Liver function tests are insufficient alone; biochemical fibrosis markers (ELF, Fib4, FibroTest) or transient elastography (TE) are more effective. Liver biopsy remains a possibility for complex cases. DC is diagnosed clinically through examination.

Treatment

There's no cure for ALD; treatment focuses on monitoring complications, abstinence, lifestyle changes (diet, weight loss), and potentially coffee consumption. Liver transplant (LT) is an option for end-stage disease. Regular monitoring for HCC and oesophageal varices is crucial. Abstinence is key to preventing disease progression and improving survival rates, even in advanced stages. Psychosocial support integrated into hepatology services enhances abstinence rates.

Hepatocellular Carcinoma

Clinical Manifestations

ALD is a leading cause of HCC globally. The annual probability of HCC is higher in patients with DC than CC, and many cases are detected incidentally or during routine surveillance.

Assessment

Diagnosis involves imaging (CT, MRI) and sometimes biopsy. A multidisciplinary approach is essential.

Treatment

Treatment depends on the stage of the disease and patient factors. Curative options include ablation, resection, or LT. Palliative options include chemoembolization, chemotherapy, and supportive care.

Prognosis

Prognosis varies drastically depending on treatment. Resection or LT offers better survival rates than palliative care.

Alcoholic Hepatitis (AH)

AH, first described in 1961, is a distinct syndrome. Patients present with jaundice following increased alcohol consumption, elevated bilirubin, and liver inflammation.

Assessment

Diagnosis involves history, examination, blood tests, and potentially biopsy and imaging to rule out other causes.

Treatment

Abstinence is essential. Hospital management includes monitoring, and in severe cases, corticosteroids (with potential risks) or N-acetylcysteine. Nutritional support via feeding tubes is also important.

Prognosis

Severe AH has high mortality, even with treatment. Abstinence is strongly linked to long-term survival. LT is being explored as a therapeutic option in selected cases.

New Developments in Treatment of AH

Research into AH treatment is ongoing, with LT emerging as a potential treatment for selected cases, offering improved survival compared to matched controls.

Conclusion

Despite high morbidity and mortality rates, research and clinical practice in integrated alcohol treatment for ALD is limited. More integrated psychosocial and pharmacological treatment pathways are needed.

Summary

Drinking too much alcohol is a big problem. It can seriously hurt your liver and even cause death. Doctors have known about this for a long time, but it's gotten worse since the 1970s because alcohol is easier to get.

Epidemiology of alcohol-related liver disease

Liver disease from alcohol is a major health concern worldwide, especially in Europe and the Americas. Many people die from this each year. In some places, deaths related to alcohol and liver problems are going up. The more alcohol a person drinks, the more likely they are to get liver problems. Other things can also increase your risk, like being overweight, having a certain type of virus, or not having a lot of money.

The spectrum of alcohol-related liver disease

Drinking too much alcohol can cause different problems with your liver. It can start with a fatty liver, and if you keep drinking, it can get worse. It can lead to cirrhosis, which is serious liver damage, and even cancer. If you stop drinking, the damage might get better.

Overview of hepatic metabolism of alcohol

Your liver works hard to get rid of alcohol. It has special tools to break down alcohol, but this process can hurt your liver cells.

How does alcohol damage the liver?

Alcohol hurts your liver in many ways. It makes your liver cells weaker and causes inflammation. This inflammation leads to scarring and can eventually cause cirrhosis and liver cancer.

Liver fibrosis and cirrhosis

Cirrhosis is a serious liver problem. It can happen slowly over many years without many obvious symptoms. Tests can help find cirrhosis early. The best treatment is to stop drinking alcohol. For some, a liver transplant might be needed. Stopping drinking is important to keep the liver from getting worse. There are ways to get help quitting.

Hepatocellular carcinoma

Liver cancer is a serious complication of liver damage from alcohol. Regular checkups and scans can help find the cancer early. Treatment depends on how serious the cancer is.

Alcoholic hepatitis (AH)

Alcoholic hepatitis is a serious liver inflammation. Symptoms include jaundice, which makes your skin and eyes yellow, and a tender liver. Stopping alcohol is essential. Some people need medicine, or even a liver transplant.

Conclusion

Liver disease from drinking too much alcohol is a big problem. Stopping drinking is the best way to treat it. There are ways to get help with stopping. More research is needed to help people with this problem.