Oxidative stress is an imbalance between pro-oxidants and antioxidants (Reviewed-[5]). Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are products of normal metabolism and can be beneficial to the host (e.g., by contributing to bacterial killing) [5]. Overproduction of ROS and/or RNS or inadequate antioxidant defenses (e.g., low levels of vitamins, selenium, mitochondrial glutathione), or both, can lead to liver injury. The stimulus for oxidative stress in the liver comes from multiple sources. In hepatocytes, CYP2E1 activity increases after alcohol consumption—in part because of stabilization of messenger RNA (mRNA). Similarly, CYP2E1 activity is increased in NAFLD. The CYP2E1 system leaks electrons to initiate oxidative stress [5]. CYP2E1 is localized in the hepatic lobule in areas of alcohol-induced liver injury. Moreover, overexpression of CYP2E1 in mice and in HepG2 cells (a human hepatoma cell line) in vitro leads to enhanced alcohol hepatotoxicity. Nonparenchymal cells and infiltrating inflammatory cells (e.g., polymorphonuclear neutrophils) are another major source of pro-oxidants that are used for normal cellular processes, such as killing invading organisms. Infiltrating neutrophils use enzyme systems such as myeloperoxidase to generate hypochlorous acid (HClO–, a halide species that causes oxidative stress) and RNS.

Moderate/severe alcoholic hepatitis (AH) is regularly associated with malnutrition. In large VA Cooperative Studies, virtually every patient with AH had some degree of malnutrition [6]. Almost 50 % of severe AH patients’ energy intake came from alcohol. Although calorie intake was frequently adequate, intake of protein and critical micronutrients was often deficient. In these VA cooperative studies, the severity of liver disease correlated with malnutrition. Patients were given a balanced 2500-kcal hospital diet. Voluntary oral food intake correlated in a stepwise fashion with 6-month mortality data. Thus, patients who voluntarily consumed more than 3000 kcal/day had virtually no mortality, whereas those consuming less than 1000 kcal/day had greater than 80 % 6-month mortality.

A classic example of micronutrient deficiency in ALD is zinc deficiency [7, 8]. Alcoholics regularly have decreased dietary intake of zinc, as well as poor absorption and increased excretion. Moreover, oxidative stress causes zinc to be released from critical zinc-finger proteins. These cumulative effects negatively impact critical zinc-finger functions. This can lead to liver injury, altered fat metabolism, impaired liver regeneration, etc., as well as produce classic clinical manifestations of zinc deficiency in humans such as night blindness or skin lesions.

The type of dietary fat consumed also appears to play an important role in the pathogenesis of ALD. Several studies have shown that dietary saturated fat protects against alcohol-induced liver disease in rodents, whereas dietary unsaturated fat, enriched in linoleic acid (LA), promotes alcohol-induced liver damage [9]. The mechanism(s) by which the combination of LA and alcohol promotes liver injury are not fully understood. LA is the most abundant polyunsaturated fatty acid in human diets and in human plasma and membrane lipids. Dietary intake of LA has more than tripled over the past century. LA can be enzymatically converted to bioactive oxidation products, OXLAMs, primarily via the actions of 12/15-lipoxygenase (12/15-LO), or non-enzymatically via free radical-mediated oxidation response to oxidative stress. OXLAMs (either alone or in conjunction with ethanol) can induce increased gut permeability and hepatic mitochondrial dysfunction in experimental ALD. Obesity can also accelerate ALD. As noted above, high fat diets rich in linoleic acid worsen ALD. We also have preliminary research showing that high fructose (sugared pop) diets worsen experimental ALD.

Alcohol, and specifically its metabolite acetaldehyde, disrupts tight junction proteins and increases gut permeability both in vitro and in vivo; and increased endotoxin levels are regularly observed in rodent models and in humans with ALD. Endotoxin stimulates the production of TNF and other proinflammatory cytokines through Toll-like receptor (TLR4) signaling, which plays a critical role in the development and progression of ALD (Fig. 13.2). Other bacteria-derived toxins, such as peptidoglycan and flagellin, may also impact TLR signaling and proinflammatory cytokine production [10]. Indeed, injected peptidoglycan increases liver injury/inflammation in alcohol-fed compared to control-fed mice, and ethanol feeding increases peptidoglycan levels [10, 11]. Moreover, chronic alcohol feeding increases hepatic TLRs and thus sensitizes hepatocytes to inflammation/injury induced by translocation of gut derived bacteria/toxins. Endotoxin not only plays a role in the fatty liver and liver injury of experimental ALD, but it also appears to play a role in hepatic fibrosis. In vitro assays as well as in vivo mixed chimerism studies show that endotoxin primes stellate cells for Transforming Growth Factor-β (TGF)-stimulated collagen production (reviewed-[12]). Thus, LPS also plays a role in fibrosis induction and progression.

Alterations in the gut microbiome likely play a major role in the development/progression of gut barrier dysfunction, endotoxemia, and liver injury/fibrosis in ALD [13]. We showed that ethanol consumption caused a time-dependent decline in the abundance of both Bacteriodetes and Firmicutes, which was accompanied by a proportional increase in Actinobacteria and Proteobacteria [14]. The stability of the normal intestinal microbiome is influenced by several factors in the luminal environment including gastric acidity, gut motility, bile salts, immunological defense factors, colonic pH and competition between microorganisms for nutrients and intestinal binding sites. An altered luminal environment may lead to modifications in the microbial composition by supporting the growth of specific genera. Thus, a major increase of Alcaligenes (an alkaline tolerant genus) correlated with an increase in fecal pH and a decrease in fecal short-chain fatty acids (SCFA). Further, some SCFAs (e.g., butyrate) have important signaling functions and epigenetic consequences, and are a critical energy source for the intestine [15]. These alterations in gut bacteria and their metabolites represent not only major mechanisms for ALD but also therapeutic targets for intervention with agents such as probiotics and prebiotics.

There are multiple other mechanisms that are likely important in ALD. ER stress, or the unfolded protein response (UPR) pathway, is activated by conditions of protein overload or increased unfolded proteins. Once triggered, this signaling pathway results in adaptation and recovery of homeostasis; however, severe or prolonged ER stress can ultimately result in cell death. Alcohol-induced ER stress is seen in experimental alcohol-feeding models in mice, micropigs, rats, and zebrafish [16–19]. ER stress has been also been reported in human patients with ALD [20, 21].

Fibrin/Extracellular Matrix plays a critical role in the progression of ALD. Fibrosis results from an imbalance between production and resorption of extracellular matrix (ECM) caused by a complex interplay between activation/transdifferentiation of hepatic stellate cells (HSCs), profibrogenic growth factors and cytokines, and alterations in the fibrin coagulation system. Hepatic injury in experimental models of liver disease often involves dysregulation of the fibrin cascade, resulting in the formation of fibrin clots that can cause hepatocellular death and induce inflammatory signaling in the liver. Inhibition of fibrinolysis by plasminogen activator inhibitor-1 (PAI-1) can cause fibrin-ECM to accumulate, even in the absence of enhanced fibrin deposition by the thrombin cascade. An imbalance in coagulation factors as well as elevated PAI-1 levels and hypofibrinolysis are common in patients with ALD [22].

Both genetic and epigenetic factors are important for disease pathogenesis and progression in ALD. The genetic variations are often associated with conformational changes in protein structures and functions due to single nucleotide polymorphisms (SNPs), whereas epigenetic changes are phenotypic changes due to altered gene expression without affecting the underlying DNA sequence. In ALD, polymorphisms of alcohol metabolizing enzymes such as ADH and CYP2E1, as well as antioxidant enzymes and cytokine coding genes, have shown strong correlation with the progression of ALD [23]. Important epigenetic modifications in ALD include microRNAs, DNA methylation, and histone modifications.

Chronic alcohol consumption can lead to a spectrum of liver injuries which can occur sequentially, separately, or simultaneously in the same patient [39]. Alcoholic steatosis is the initial and most common manifestation of alcoholic liver disease. It is characterized histologically by both microvesicular and macrovesicular fat accumulation within the hepatocytes, with minimal inflammatory response or hepatic fibrosis [40]. Patients with steatosis are usually asymptomatic. They typically have normal to very mild elevations of their liver enzymes, such as GGT, ALT, and AST. Serum bilirubin and markers of hepatic function (international normalized ratio (INR), albumin levels) also tend to be normal. Alcoholic steatosis is reversible with abstinence [41].

Early studies by Dr. Charles Lieber using volunteers demonstrated the relative ease with which alcohol consumption causes fatty liver [42, 43]. Indeed, volunteers who drank heavily (46 % of calories as alcohol) for 1–2 weeks exhibited fatty liver on biopsy.

A subset of people who continue to drink heavily will develop AH. Why only a subset of people develop more advanced and ominous disease is unclear, but probably relates at least in part to risk factors. These risk factors can be modifiable or nonmodifiable (Table 13.2). The most important modifiable risk factor is continued drinking. Nonmodifiable risk factors include sex (females are at higher risk) and genetics (certain polymorphisms, as discussed previously in the Mechanisms section). Alcoholic Hepatitis is a necro-inflammatory process characterized by predominant neutrophilic infiltration, ballooning degeneration of hepatocytes, and hepatocyte necrosis [44]. Acutely, the development of alcoholic hepatitis is associated with a significant increase in mortality and the potential to develop portal hypertension and its complications, even without developing major fibrosis [45]. In the long term, for those who survive, this disease process is associated with an accelerated course of fibrosis progressing to cirrhosis in 40 % of cases [46]. These distinctions in the natural progression of alcoholic liver disease also have therapeutic implications, explaining why a subset of alcoholics with inflammatory features are candidates for treatment with anti-inflammatory agents (i.e., corticosteroids and pentoxifyline) in an attempt to reduce proximal mortality, whereas patients without major inflammatory features may be better candidates for treatment geared toward reducing long-term hepatic injury/cell death, hepatic dysfunction, or possibly enhancing liver regeneration.

Due to the important acute prognostic implications of alcoholic hepatitis and possible subsequent cirrhosis , multiple scoring systems have been developed to assess the severity of liver disease in terms of patient survival in order to assign patients to proven treatment modalities. The Child-Turcotte-Pugh (CTP) , the oldest scoring system, incorporates the serum bilirubin level, albumin level, PT, and the severity of ascites and hepatic encephalopathy in assigning a numerical score that is used to categorize patients (class A = scores 1–6, class B = scores 7–9, class C = scores 10–15), with a higher score denoting more severe disease [47]. It is the most widely used scoring system to evaluate severity of cirrhosis . Since 2002, the United Network for Organ Sharing (UNOS) has utilized the MELD score to grade the severity of liver disease in patients awaiting liver transplant. This represents a more objective analysis, utilizing only the serum bilirubin, creatinine, and INR [48]. This scoring system has been validated in multiple studies to accurately predict the 3 month mortality of patients with liver disease, especially those patients awaiting liver transplantation [49].

The CTP and MELD score are proven modalities to assess the gravity of liver disease due to a variety of causes. However, due to the particularly inflammatory nature and high degree of early mortality associated with acute alcoholic hepatitis , varying scoring systems have been, and continue to be, specifically developed and used in the assessment of this form of liver disease. Since its development in the in the late 1970s, the Discriminant Function (DF) of Maddrey, which incorporates the serum bilirubin and PT, has been widely used to predict short-term mortality in patients with alcoholic hepatitis and to select in an evidence-based manner, those who are likely to benefit from treatment with corticosteroids [50]. Patients are classified into those who have nonsevere alcoholic hepatitis (DF < 32) and those who have severe alcoholic hepatitis (DF > 32). As the proximal early mortality is 10 % versus 30–60 % in the groups with and without treatment, respectively [51], the latter group is usually treated with corticosteroid therapy unless contraindicated [52]. A useful link to calculate 90-day mortality in acute alcoholic hepatitis, based in the MELD score, can be found at http://​www.​mayoclinic.​org/​medical-professionals/​model-end-stage-liver-disease/​meld-score-90-day-mortality-rate-alcoholic-hepatitis. Other specific scoring systems include the Glasgow alcoholic hepatitis score (GAHS) which is a composite of scores related to patient age, leukocyte count, serum urea levels, serum bilirubin level, and PT ratio [53], with a score ≥9 signifying poor prognosis. In this study, patients with both, a DF > 32 and a GAHS > 9, had 28 day survival, if corticosteroid-treated versus corticosteroid-untreated, of 78 % vs. 52 %, and an 84-day survival of 59 % versus 38 %, respectively. If the GAHS was less than 9, there was no difference in outcome between the corticosteroid treated or untreated groups. A more recent scoring system, the ABIC score [(age × 0.1) + (serum bilirubin × 0.08) + (serum creatinine × 0.3) + (INR × 0.8)], has shown promising results in the prediction of 3 month mortality in patients with alcoholic hepatitis [54]. This model stratifies the severity of alcoholic hepatitis as low (score < 6.71), intermediate (score: 6.71–8.99), and high (score ≥ 9.0). Theses scores correspond to a 90 day survival of 100 %, 70 %, and 25 % respectively, and 1-year survival of 97 %, 64 % and 33 % respectively.

The Lille score is unique in that it is not only clinically useful in assessing the severity of patients presenting with alcoholic hepatitis , but it is also used to assess the response of patients with more severe forms of alcoholic hepatitis being treated with systemic corticosteroids. The score includes six variables: age, albumin level, bilirubin level at day 0, bilirubin level at day 7, PT, and the presence of renal insufficiency [55]. A score of <0.45 predicts a 6 month survival of 85 ± 2.5 % while a score >0.45 predicts a 6 month survival of only 25 ± 3.8 % (sensitivity and specificity at 81 % and 76 %, respectively) [56]. Patients with a score of ≥0.45 on day 7 while on therapy with corticosteroids (null responders), which represent close to 40 % of the corticosteroid treated patients, are recommended to be switched over to alternative forms of treatment because they will not benefit from the continuation of corticosteroid therapy.

Interventions for ALD patients reside on a continuum (Fig. 13.3). All patients should control the modifiable risk factors of alcohol use, obesity, and smoking. Most with advanced disease will benefit from treating malnutrition. Some may need pharmacotherapy. Only a few will be transplant candidates, and they are patients with severely decompensated ALD who have stopped drinking.