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Liver Fibrosis in Alcoholic Liver Disease Ramon Bataller, MD, PhD1

Bin Gao, MD, PhD2

1 Division Gastroenterology and Hepatology, Department of Medicine,

University of North Carolina at Chapel Hill, North Carolina 2 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

Address for correspondence Ramon Bataller, MD, PhD, Division Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, NC 27599 (e-mail: [email protected]).

Abstract

Keywords

► ► ► ►

alcoholic hepatitis hepatic stellate cells steatohepatitis animal models

Excessive alcohol consumption causes a wide spectrum of liver disease, ranging from simple steatosis to severe forms of liver injury such as steatohepatitis, liver fibrosis, cirrhosis, and liver cancer. Moreover, alcohol consumption also accelerates liver fibrosis in patients with other types of liver diseases such as viral hepatitis and nonalcoholic fatty liver disease. Virtually all clinical complications of alcoholic liver disease occur in patients with established fibrosis and cirrhosis, thus making fibrosis a key parameter for treatment and prognosis of patients. Here, the authors review diagnosis, management, and antifibrotic therapy of alcoholic liver fibrosis. They discuss both the unique features of alcoholic liver fibrosis and the similarities to liver fibrosis from other etiologies, and review molecular pathogenesis and animal models. Finally, future directions for basic and clinical research on alcoholic liver fibrosis are proposed.

Alcohol abuse is one of the main causes of preventable disease. The Global Status Report on Alcohol and Health 2014 from the World Health Organization indicates that alcohol abuse accounts for 50% of cirrhosis worldwide. Therefore, alcohol abuse is probably the main cause of advanced liver fibrosis. As a consequence, alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. Despite its burden, the incidence, natural history, and modifying factors of ALD remain largely unknown. Most patients are diagnosed at advanced stages of the disease; there are few active programs of early detection. Alcoholic liver disease encompasses a range of disorders including simple steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In addition, patients with advanced ALD (in most cases cirrhosis) and active drinking can develop an episode of acute-onchronic liver injury—alcoholic hepatitis (AH),1 which bears a poor prognosis. Over the last several years, important advances have been made in the understanding of the cellular and molecular mechanisms of liver fibrosis in ALD.2 Novel experimental models of ALD combining continuous and binge alcohol administration as well as translational studies in

Issue Theme Liver Fibrosis; Guest Editors, Robert Schwabe, MD, and Ramon Bataller, MD, PhD

human samples have uncovered several key cellular and molecular drivers lining alcohol-induced liver damage, inflammation, and fibrogenesis.3,4 In this review, we discuss the burden, pathogenesis, diagnosis, and management of fibrosis in the setting of ALD from the moderate stages to cirrhosis, and in alcohol hepatitis. We also discuss the fact that alcohol abuse can be a modifying factor for fibrosis in other types of liver diseases. Future directions are also proposed.

Liver Fibrosis in ALD: Incidence, Natural History, and Modifying Factors Liver cirrhosis is the 12th leading cause of death in the United States, with 30,000 deaths annually.5 Among all cirrhosis deaths in 2007, 48% were alcohol-related. Although there is no doubt that alcohol is the main cause of cirrhosis, the weight of alcohol abuse as a cause of moderate/silent liver fibrosis is unknown. Recent studies in France using noninvasive methods to estimate the presence of liver fibrosis in the general population have shown that ALD and nonalcoholic fatty liver disease (NAFLD) together account for more than 88% of cases.6 Importantly, in one third of the patients, alcohol

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0035-1550054. ISSN 0272-8087.

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Semin Liver Dis 2015;35:146–156.

Bataller, Gao

Fig. 1 The spectrum of alcoholic liver disease (ALD) and the main determinants that modify fibrosis progression. The percentage represents the patients who progress from one stage to the next. Most patients with persistent alcohol abuse develop some degree of hepatic steatosis. If the alcohol abuse persists, liver fibrosis progressively develops, ultimately resulting in cirrhosis. Cirrhosis can lead to severe complications related to portal hypertension (ascites, variceal bleeding, and encephalopathy) and bacterial infections, as well as predisposes to hepatocellular carcinoma (HCC). The development of alcoholic steatohepatitis predisposes to progression to advanced liver fibrosis; when it develops in patients with severe disease can result in alcoholic hepatitis. The box in the upper right describes the environmental and genetic factors known to influence the natural history of ALD. HCV, hepatitis C virus; HBV, hepatitis B virus; HIV, human immunodeficiency virus.

abuse and metabolic syndrome coexist, suggesting that many patients have both types of fatty liver disease. Alcoholic liver disease comprises a broad spectrum of disease ranging from asymptomatic fatty liver to ASH, progressive fibrosis, cirrhosis, and superimposed HCC (►Fig. 1). Up to 90% of patients with heavy alcohol intake have fatty liver,7 which is usually asymptomatic and rapidly reversible with abstinence. Continued heavy alcohol consumption, however, may lead to inflammation of the liver characterized by the infiltration of polymorphonuclear (PMN) cells and hepatocellular damage, both of which define ASH. This early form of ASH is frequently overlooked in primary care setting, in part due to the lack of a widely accepted nomenclature. We are currently conducting an observational international study to further characterize this early form of ASH from a clinical, histological, and molecular point of view, to compare it with the severe forms seen in AH, and to improve the current nomenclature (CLASH Study: Clinical, Histological and Molecular Characterization of Two Subtypes of Alcoholic Steatohepatitis). Eventually, patients with early form of ASH may develop liver fibrosis deposition (20–40%)—typically in a perisinusoidal chicken-wire pattern—and cirrhosis (8–20%), which confers a high risk of complications (such as ascites, variceal bleeding, hepatic encephalopathy, renal failure, and bacterial infections).8 Patients with AH also develop the characteristic pattern pericellular and sinusoidal chickenwire fibrosis (►Fig. 2).9 When this pattern is diffuse, the

fibrosis is defined as panlobular. This pattern of fibrosis is not exclusive of ALD and can be also seen, in a lesser extent, in patients with NAFLD.10 The clinical implications of chickenwire type of fibrosis are not well known. It distorts the normal

Fig. 2 Panlobular fibrosis in a patient with severe alcoholic liver disease showing a typical “chicken-wire” pattern. Representative photomicrograph of a trichromic staining from a patient with an episode of alcoholic hepatitis. The liver biopsy was performed using a transjugular approach. Besides severe steatosis, the fibrotic tissue accumulates around hepatocytes and sinusoidal cells forming a chicken-wire pattern. Seminars in Liver Disease

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liver architecture and probably contributes to increase intrahepatic resistance to blood flow. In patients with AH, the prognosis of patients with predominant panlobular fibrosis is better than in those with bridging fibrosis/cirrhosis.9 This can be because this type of fibrosis represents a less advanced stage of liver disease; it is also more susceptible to degradation by metalloproteinases in patients with prolonged abstinence. Future studies should explore this hypothesis. Moreover, patients with alcoholic cirrhosis are at a high risk to develop HCC, however, this incidence is lower than that in cirrhotic patients due to viral hepatitis, and does not completely disappear after abstinence.11 Patients with underlying severe fibrosis or cirrhosis and heavy alcohol intake may present a form of acute-on-chronic liver damage called AH. This is characterized by an abrupt rise in serum bilirubin levels, jaundice, and liver-related complications1 Alcoholic liver disease results from a complex interaction of behavioral, environmental, and genetic factors. Although a positive correlation between cumulative alcohol intake and degrees of liver fibrosis has been reported, extensive variability in the histological response to alcohol abuse exists in individuals.12 At similar levels of ethanol consumption, some patients only develop macrovesicular steatosis, while others develop progressive fibrosis and cirrhosis. The main environmental factors that promote the progression of liver fibrosis in patients with alcohol abuse include obesity and cigarette smoking.13 The role of metabolic factors, including insulin resistance, is unclear, although some reports suggest that such factors might also favor progression of fibrosis.14 Interestingly, many epidemiologic studies suggest that consumption of coffee and potentially other caffeinated beverages may reduce liver fibrosis in patients with viral hepatitis or ALD.15–17 The amount of recent daily alcohol consumption is the main determinant of the risk of advanced fibrosis and cirrhosis among heavy drinkers.18 Traditionally, it was considered that a consumption of 60 g/d in men and 40 g/d in women conferred a risk of significant fibrosis. However, in a metaanalysis of daily consumption levels in relation to cirrhosis, patients consuming 25 g/d of ethanol a day were at higher risk of cirrhosis than nondrinkers.19 Genetic factors are also known to influence the organ specificity of alcohol-related harmful effects.20 While some patients with heavy alcohol consumption develop ALD, others mainly suffer from alcoholrelated disorders of the pancreas, heart and nervous system.21 Studies in families showed variations in the susceptibility to ALD between different ethnic groups, suggesting that genetic factors are important determinants of disease risk. Twin studies also suggest a major role for genetic predisposition in the susceptibility to ALD.22 Epidemiological studies suggest that several genetic factors influence the severity of steatosis and oxidative stress, and that the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis also modulate an individuals’ propensity to progress to advanced ALD.23 Genes encoding the main alcohol-metabolizing enzymes (alcohol dehydrogenase [ADH], acetaldehyde dehydrogenase [ALDH], and CYP2E1) and some other proteins involved in the toxic effects of alcohol and its metaboSeminars in Liver Disease

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lites on the liver, such as antioxidants and proinflammatory cytokines, have been the focus of investigation. Genetic factors that influence the activity of these enzymes and the rate of alcohol metabolism have also been extensively studied.24 Owing to the fibrogenic potential of acetaldehyde, genetic variations in the rate of generation of acetaldehyde could explain the differences in the susceptibility of individuals to ALD after abusive alcohol consumption. Although polymorphisms in alcohol-metabolizing enzymes (mainly in ADH and ALDH) are accepted to be involved in an individual’s susceptibility to alcoholism, their role in the progression of ALD remains inconclusive.24 A meta-analysis of studies on the association between alcoholism and alcohol-induced liver damage highlighted the heterogeneity of the case-control studies that investigated alcohol-metabolizing enzyme polymorphisms.25 In addition to the host, oral and intestinal microbiota are known to metabolize alcohol, and interindividual differences in the intestinal microbiome might explain differences in the biological effects of alcohol.26 It has also been proposed that alcohol’s effects on the gut–brain axis may affect behavioral patterns related to ALD such as depression, anxiety, and alcohol craving.27 In addition, polymorphisms in genes that encode proinflammatory cytokines involved in the pathogenesis of ALD have also been examined. Although a single nucleotide polymorphism located in the promoter region of tumor necrosis factor, which increases production of this cytokine, is associated with severe steatohepatitis, this finding has not yet been confirmed by other studies.28 Polymorphisms in the genes encoding IRAK-M, interleukin- (IL-) 1β, and IL-1 receptor antagonists, IL-2, IL-6, and IL-10 have also been implicated in modifying the progression of ALD.28–30 Moreover, studies have also investigated the role of genetic variation in factors involved in lipopolysaccharide-induced intracellular pathways, including CD14 and toll-like receptor 4 (TLR4), as potential risk factors for ALD.31 Differential expression of genes belonging to these pathways could alter the inflammatory and fibrogenic response of the liver after prolonged alcohol intake. Patients with polymorphisms that result in low activity of superoxide dismutase and glutathione transferase (two potent antioxidant enzymes) are also at risk of developing severe ALD.32,33 Finally, several recent studies indicated that variations in palatin-like phospholipase domain-containing protein 3 (PNPLA3) gene strongly influence the development of advanced liver fibrosis among Mexican and Caucasian populations.34–37 Although PNPLA3 polymorphisms can be considered to be the only confirmed and replicated genetic risk factor for ALD, genome-wide association studies are needed in this patient population.

Alcohol as a Modifying Factor of Fibrosis in Other Types of Liver Disease Heavy alcohol consumption is known to negatively influence fibrosis progression in other types of liver disease. Alcohol consumption is a common comorbidity in patients with hepatitis C and B; it may result in synergistic injury, with accelerated rates of fibrosis and the development of cirrhosis

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Animal Models of Alcoholic Liver Fibrosis Early studies from Dr. Lieber’s group reported that ad libitum feeding with a Lieber-DeCarli ethanol diet for up to 8 years induced significant liver fibrosis in baboons46; however, ad libitum feeding with an ethanol diet only induced steatosis and mild liver injury without significant fibrosis in rats and mice. Later, Drs. Tsukamoto and French developed a model with intragastric infusion of an ethanol diet, which induced more severe steatosis and liver injury in rodents, but fibrosis was mild. Accumulating evidence suggests that “second” or “multiple” hit(s) plus alcohol are required to induce significant fibrosis in mice. The common second or multiple factors include high fat diet (HFD), binge ethanol consumption, and hepatotoxin (e.g., carbon tetrachloride [CCl4]) administration. There are two recently developed animal models that can be useful to investigate alcohol-induced liver fibrosis in rodents: HFD plus ethanol feeding and exposure to low doses of ethanol plus CCl4 or ethanol plus low doses of CCl4.

Hybrid Model of HFD Plus Ethanol Feeding Dr. Tsukamoto’s group recently developed several hybrid models, which include ad libitum a solid diet in high fat and high cholesterol, followed by intragastric infusion of ethanol and HFD diet with or without binge ethanol.47,48 Such combination feeding induced significant steatohepatitis and liver fibrosis. This new model represents a new advance in the field and is a valuable tool to study the pathogenesis of liver fibrosis caused by alcohol, HFD, and cholesterol. The

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main limitation of this model is related to the need to insert an intragastric tube feed, which is technically challenging and requires experienced personnel and sophisticated equipment.

Exposure to Low Doses of Ethanol Plus CCl4 or Ethanol Plus Low Doses of CCl4 Chronic administration of CCl4 is the most commonly used liver fibrosis model. CCl4 is a hepatotoxin that is metabolized by the CYP2E1 enzyme in hepatocytes to generate oxidative stress and subsequently damages hepatocytes. Chronic injection of CCl4 resulted in chronic hepatocyte injury, liver inflammation, and liver fibrosis, which represents a liver fibrosis model induced by chronic liver injury. It is well known that ethanol feeding enhances CCl4 metabolism by induction of cytochrome P450 2E1 expression, and subsequently, enhances CCl4-induced liver injury and liver fibrosis. To rule out this enhanced liver injury effect, we generated similar levels of liver injury in ethanol-fed and pair-fed groups by injecting pair-fed mice with a higher dose of CCl4.49 The progression of liver fibrosis was still much faster in ethanol-fed mice than in pair-fed mice even when similar levels of liver injury (serum levels of ALT) were achieved in both groups by injection of a higher dose of CCl4 in pair-fed mice. Additionally, Dr. Nagy’s group recently established a mouse model of liver fibrosis by administrating CCl4 plus moderate ethanol intake, at a level not sufficient to induce CYP2E1 or cause liver injury by itself.50 Because both CCl4 and ethanol induce hepatocyte damage through some common mechanisms such as generation of oxidative stress, combining ethanol with CCl4 administration may be a useful model to achieve more profound alcohol-induced liver fibrosis.51,52 However, the possibly strong influence of CCl4 on the phenotype needs to be considered when interpreting data from this model.

Pathogenesis of Fibrosis in ALD and Targets for Therapy Liver fibrosis is a wound-healing response to practically any type of chronic liver damage, including ALD, which is characterized by excessive accumulation of collagen and other extracellular matrix (ECM) proteins.53,54 The specific composition of the fibrotic tissue in ALD are not well known, yet collagen I is probably the most abundant ECM protein.55,56 Future proteomic studies should identify the ECM proteins that accumulate in patients with ALD, especially in typical patterns such as chicken-wire fibrosis. It is generally accepted that activation of hepatic stellate cells (HSCs) is a key event to develop liver fibrosis by producing extracellular matrix proteins; other cell types such as portal fibroblasts and bone marrow-derived myofibroblasts may also contribute to liver fibrogenesis to a lesser extent.57,58 Although a key contribution of HSCs to ECM production and the myofibroblast pool in alcoholic liver fibrosis has not been formally proven, there is little doubt that HSCs play an important role in this setting, and that they are responsible for the perisinusoidal chickenwire fibrosis seen in ALD. Over the last four decades, a wide Seminars in Liver Disease

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and HCC.38,39 Various mechanisms have been proposed, including alcohol’s effect on viral replication, virus-related cytotoxicity, oxidative stress, and immune modulation. Patients with metabolic syndrome often have excessive alcohol consumption. Nonalcoholic fatty liver disease is increasingly recognized as the downstream hepatic consequence of the metabolic syndrome. Well-known risk factors for NAFLD include insulin resistance and hypertriglyceridemia. Although the consumption of small amounts of alcohol may improve peripheral insulin resistance and are associated with less-severe lesions in patients with NAFLD,40,41 heavy alcohol consumption has been shown to worsen NAFLD at various stages of the disease, both in animals and in humans.42 There is evidence that the impact of alcohol consumption on the development of NALFD is dose dependent.40 The degree of liver fibrosis in NAFLD also increases with alcohol consumption. Patients with high-risk alcohol consumption and obesity have almost a twofold risk of developing cirrhosis.40 Alcohol abuse is also a modifying factor accelerating the clinical course of other types of liver disease. Patients with hereditary hemochromatosis who drink more than 60 g/d of alcohol are 9 times more likely to develop cirrhosis than abstainers.43 In patients with primary biliary cirrhosis, even moderate alcohol consumption (30 g/d) is an independent predictor of advanced PBC stage.44 Finally, alcohol abuse is known to favor drug-induced liver injury such as in acetaminophen overdose.45 Thus, alcohol consumption should be discouraged in patients with any type of chronic liver disease.

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variety of mechanisms have been identified to promote HSC activation and liver fibrogenesis during chronic liver injury.53,54,57 Many of these mechanisms are commonly involved in liver fibrogenesis in ALD and other types of liver diseases such as viral hepatitis and NASH. These common mechanisms include hepatocyte death, inflammation, and activation of Kupffer cells (►Fig. 3).53,54,57,59 Here, we mainly discuss some unique mechanisms that contribute to alcoholic liver fibrosis. First, it is well established that ethanol is primarily metabolized in hepatocytes, followed by generation of acetaldehyde and oxidative stress, which cause hepatocellular damage and liver fibrosis. Second, alcohol, its metabolite acetaldehyde, and their byproducts (e.g., adducts including malondialdehyde, 4-hydroxynonenal, and malondialdehyde-acetaldehyde,) can promote liver fibrogenesis by directly activating HSCs and by stimulating immune cells to produce profibrogenic mediators.60–62 Acetaldehyde, the first ethanol metabolite, has been shown to directly stimulate HSCs to produce collagen I in vitro.62 ALDH2-deficient mice, which are unable to efficiently metabolize acetaldehyde and have high levels of acetaldehyde after alcohol feeding, are more susceptible to ethanol plus CCl4-induced liver fibrosis.60 Acetaldehyde is very active and can react quickly with various cellular components to form several types of adducts. These acetaldehyde-associated adducts not only directly target HSCs to promote their activation, but also stimulate Kupffer cells and endothelial cells to produce profibrogenic mediators, thereby promoting HSC activation.62 Third, chronic alcohol consumption induces gut bacterial overgrowth and dysbiosis, followed by increasing gut permeability and translocation of bacteria-derived products into the liver to promote liver fibrosis.63,64 Finally, chronic alcohol consumption may promote liver fibrosis by blocking several antifibrotic pathways. For example, natural killer (NK) cells play an important role in inhibiting liver fibrogenesis by killing activated HSCs or

producing interferon-γ that induces HSC death and cell-cycle arrest.65,66 Chronic alcohol consumption markedly attenuates the antifibrotic functions of NK cells, thereby exacerbating liver fibrogenesis.49 Over the last 30 years, a large number of potential therapeutic targets for liver fibrosis have been identified. Although we still lack approved antifibrotic therapies for the liver (see “Antifibrotic Therapies in the Liver” by Mehal and Schuppan in this issue), antifibrotic treatment is receiving increased attention with several ongoing and some completed trials (see ClinicalTrials.gov).67,68 However, the majority of patients included in these trials are those with chronic hepatitis B or C infection. Patients with ALD were scarcely included in these trials because ALD patients often have an active addiction and extrahepatic complications in organs such as the pancreas, heart, nervous system, and kidney. In general, most of the identified antifibrotic therapeutic targets should also be applicable in ALD patients. These targets include elimination of the causes of injury and their mediators, inhibition of inflammation, inhibition of HSC activation, and induction of HSC death.67 In addition, there are some antifibrotic therapeutic targets, which may be unique for ALD patients. First, alcohol consumption causes gut bacterial overgrowth and dysbiosis and subsequent disruption of gut epithelial integrity. Thus, targeting gut bacteria and gut epithelial cells may be a unique approach for the antifibrotic treatment in ALD patients. Second, antifibrotic function of NK cells is suppressed in ALD patients, so restoration of NK cell function may be another specific strategy to treat liver fibrosis in these patients. Third, IL-22 is a recently identified cytokine that is probably the only cytokine produced by immune cells, but do not target immune cells. Instead, IL-22 mainly targets hepatocytes and HSCs in the liver, exerting hepatoprotective and antifibrotic functions.69 Hepatic expression of IL-22 is highly elevated in patients with viral hepatitis,70 but not in those

Fig. 3 Pathogenesis of alcoholic liver fibrosis. Several pathways contribute to the pathogenesis of alcoholic liver fibrosis: (1) Ethanol is primarily metabolized in hepatocytes. Oxidative stress and acetaldehyde generated from ethanol metabolism cause hepatocyte damage and activation of Kupffer cells, which leads to the release of a variety of mediators and the subsequent induction of hepatic stellate cell (HSC) activation. (2) Acetaldehyde and its byproducts (e.g., malondialdehyde, 4-hydroxynonenal, and malondialdehyde-acetaldehyde), directly target HSCs and upregulate the expression of collagens in these cells. (3) Alcohol consumption causes gut bacterial overgrowth and dysbiosis, and subsequent elevation of bacteria-derived products in the liver to promote liver fibrosis. (4) Chronic alcohol consumption suppresses the antifibrotic pathways such as natural killer cell functions. Seminars in Liver Disease

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with alcoholic hepatitis.71 Therefore, patients with alcoholic hepatitis, but not viral hepatitis, may be sensitive to the antifibrotic treatment of IL-22.

Diagnosis of Fibrosis in Patients with ALD In its early stages, ALD is a silent disease and can only be detected by laboratory tests or imaging techniques.72 There are few programs aimed at early detection of ALD at its asymptomatic stages. Some patients with early ALD can show stigmata of alcohol abuse such as bilateral parotid gland hypertrophy, muscle wasting, malnutrition, Dupuytren’s sign, and signs of peripheral neuropathy. In patients with cirrhosis, most physical findings are not specific of the etiology. However, some signs such as gynecomastia and extensive spider angiomas may be more frequently seen in those with alcohol as the main cause of liver disease. The diagnosis of ALD is frequently suspected upon documentation of excess alcohol consumption (> 40–50 g/d) and the presence of clinical and/or biological abnormalities suggestive of liver injury. Laboratory blood tests such as mean corpuscular volume, gamma glutamyl transpeptidase (GGT), and aspartate aminotransferase (AST) can indicate early ALD whereas advanced ALD is suspected if there is decreased albumin, increased international normalized ratio, elevated bilirubin level, or low platelet count. There are several laboratory markers that estimate persistent alcohol intake. Among them, carbohydrate-deficient transferrin (CDT) and GGT are the most frequently used markers to detect previous alcohol consumption.73 In patients with ALD, the AST/ALT ratio typically is > 1.74 This ratio is typically > 2 in AH and can also be found in patients with advanced cirrhosis regardless of the etiology. The most definitive method to detect liver fibrosis in patients with alcohol abuse is based on histological analysis.75 However, a liver biopsy is not clearly indicated in patients with early stages of ALD or when the presence cirrhosis is clearly suggested by clinical, analytical, and imaging data. The liver biopsy can be done percutaneously in most patients and requires a transjugular approach in patients with a low platelet count and/or a prolonged prothrombin time. The precise indications of liver biopsy are not well established in routine practice. However, it is indicated in patients with aggressive forms of ALD such as AH requiring specific therapies (e.g., corticosteroids and/or pentoxifylline) and in patients with other cofactors suspected of contributing to liver disease. In the setting of clinical trials, the assessment of liver histology by performing a liver biopsy is still recommended. The typical findings in patients with ALD include steatosis, hepatocellular damage (ballooning and/or Mallory-Denk bodies), an inflammatory infiltrate basically composed of PMN cells that predominates in the lobules, and a variable degree of pericellular and lobular fibrosis that may progress to cirrhosis (►Fig. 2).76 The histological features including the pattern of fibrosis in patients with ASH are similar to that described in patients with NASH. In obese patients with alcohol abuse, more ballooning degeneration, portal inflammation, Mallory-Denk bodies, and higher stage of fibrosis favor diagnosis of ASH, while higher grade of steatosis and

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absence of extensive neutrophilic portal inflammation support NASH diagnosis.77 For the assessment of liver fibrosis in patients with ALD, there are noninvasive methods including serum markers and liver stiffness measurement.78 Most noninvasive tests have been largely validated in patients with hepatitis C, while only a few studies evaluated the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. These include hyaluronic acid, FibroTest (FibroSure), FibroMeter A, Hepascore, Forn’s Score, the AST-to-Platelet Ration Index (APRI), and yjr Fibrosis 4 (FIB4) Index.79 Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of ALD patients.79 They are useful to distinguish between mild and severe fibrosis, but have limited utility in intermediate degrees of fibrosis. Transient elastography (Fibroscan) is commonly used to assess fibrosis in patients with chronic liver disease. This device was recently approved by the Food and Drug Administration in the United States. In patients with ALD, liver stiffness correlates with the degree of fibrosis.80 Elevated liver stiffness values in patients with ALD and AST serum levels > 100 U/L should be interpreted with caution because of the possibility of falsely elevated liver stiffness as a result of superimposed ASH (caused by swelling rather than fibrosis). Moreover, recent alcohol consumption can also elevate liver stiffness, perhaps related to the vasodilatory effects of alcohol.81 Imaging techniques can also be used to assess the severity of ALD. Ultrasonography, magnetic resonance imaging, and computed tomography are useful to detect fatty liver, advanced fibrosis/cirrhosis, as well as signs of portal hypertension.82 Moreover, they are useful for the screening and assessment of complications such as ascites and portal vein thrombosis. Among those methods, ultrasound is the most used due to its low cost. However, its sensitivity and specificity is low especially when steatosis is mild. Magnetic resonance imaging and MR spectroscopy are reliable tools for assessing the amount of steatosis, but their use is limited by high cost.83

Liver Fibrosis in Alcoholic Hepatitis Alcoholic hepatitis is a clinical syndrome characterized by new-onset jaundice and/or ascites in the setting of ongoing alcohol abuse and underlying ALD.1 Currently, AH is considered a form of the newly described entity of acute-on-chronic liver failure. In some patients, the episode of AH is the first manifestation of a silent ALD, whereas in others it is an exacerbation of a known alcoholic cirrhosis. Alcoholic hepatitis should be distinguished from early ASH in fully compensated patients. This early form of ASH shows a similar degree of steatosis and inflammatory changes, but it has a much better prognosis because the liver synthetic function is preserved.72,84 The diagnosis of AH is made on clinical grounds based on a history of excessive alcohol use with the typical physical exam and laboratory findings. Liver biopsy may be helpful to establish the presence of ASH and has been endorsed in recent clinical practice guidelines.72,85,86 Biopsy is particularly valuable in the setting of atypical clinical characteristics Seminars in Liver Disease

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or when the diagnosis remains in doubt. A transjugular route is often preferred due to frequent coexisting ascites and/or coagulopathy. Infections, particularly spontaneous bacterial peritonitis, must be ruled out as they can present with similar clinical findings (abdominal pain, fever, leukocytosis) and because they are a contraindication to specific therapy with corticosteroids. Alcoholic hepatitis is characterized by a profound distortion of liver architecture, mainly due to bridging fibrosis and portal/expansive fibrosis. Moreover, these patients present a typical pattern of fibrosis (pericellular and perisinusoidal) that is known as “chicken wire” (►Fig. 2). The resulting portal hypertension favors the development of complications such as ascites, renal failure, infections, and encephalopathy, and is associated with a poor prognosis.87 Recently, we performed a large multicenter study to develop a histological scoring system capable of predicting short-term survival in patients with AH.9 The resulting Alcoholic Hepatitis Histological Score (AHHS) comprises four parameters that are independently associated with patients’ survival: fibrosis stage, PMN infiltration, type of bilirubinostasis, and presence of megamitochondria. By combining these parameters in a semiquantitative manner, we were able to stratify patients into low, intermediate, or high risk for death within 90 days.9 Regarding the pattern of fibrosis, we found that the presence of bridging fibrosis or cirrhosis was associated with a poor prognosis. This may be partially because accumulation of ECM proteins in fibrosis/ cirrhosis promotes ductular reaction (possible hepatic progenitor cell proliferation), but limits hepatocyte proliferation, resulting in impairment of normal liver regeneration.88

The mechanisms of liver fibrosis in the setting of AH are not well known, partially due to the lack of a well-established animal model. In a translational study in human samples, we found that AH was characterized by a massive presence of fibrotic tissue and activated α-SMA positive myofibroblasts. Importantly, the percentage of positive area of fibrosis closely correlated with the degree of portal hypertension, suggesting that an exaggerated fibrogenic response to injury is a key pathogenic event in this disease (►Fig. 4).89 Gene-expression analysis of patients with AH revealed a marked upregulation of genes encoding procollagen, but also of fibrogenic mediators such as tissue inhibitor of metalloproteinases (TIMP-1), transforming growth factor β1 (TGFβ1), and ut-PA. Because fibrosis and the resulting portal hypertension negatively impact the survival of these patients, maneuvers aimed at decreasing the accumulation of myofibroblasts and collagen expression should be tested in clinical trials.

Antifibrotic Approaches in Patients with ALD There are few studies assessing strategies to slow down or even reverse fibrosis progression in patients with ALD. The lack of studies is influenced by intrinsic difficulties to perform clinical trials in patients with active addition (i.e., poor compliance). Moreover, patients enrolled in clinical trials are likely to reduce their alcohol intake, which can attenuate fibrosis progression. The fact that placebo-treated patients in large trials showed reduction in fibrosis supports this assumption.90 To date, the only effective therapy to reverse fibrosis in patients with ALD is abstinence from alcoholic

Fig. 4 Fibrosis and myofibroblasts accumulation in alcoholic hepatitis (AH). Representative photomicrographs of normal human livers and livers from patients with AH stained with Sirius red (A) and α-SMA (B). Correlation between the accumulation of myofibroblast cells and the degree of fibrosis as assessed by quantification of positive area for Sirius red (C). Correlation between the percentage of area with Sirius red staining and the degree of portal hypertension (D). (From Colmenero et al, with permission 89). Seminars in Liver Disease

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beverages. Total abstinence from alcohol consumption generates better clinical outcome of liver disease, this being the most important factor determining long-term survival in alcohol-related cirrhosis.91 Therefore, promoting alcohol abstinence is of paramount importance for patients with ALD. Besides counseling, anticraving drugs such as baclofen, a GABA-B agonist, are effective and safe in patients with ALD. The use of other drugs such as disulfiram or naltrexone is hampered by potential hepatotoxicity.92 There are few systematic reports indicating that alcohol abstinence is the main determinant of outcome in patients with compensated ALD.93 Moreover, isolated reports indicate that alcohol abstinence is followed by fibrosis regression.94 Prospective studies are needed to uncover the genetic and environmental factors involved in fibrosis resolution. There are few reports investigating the efficacy of targeted therapies in patients with ALD. Most ongoing clinical trials are focused on AH, which is characterized not only by fibrosis but also by profound liver failure and cholestasis. In patients with compensated ALD, few attempts have been made to attenuate fibrosis progression. Most approaches have focused on antioxidant drugs and drugs that have intrinsic antifibrotic properties.95 Antioxidants such as S-adenosyl-L-methionine, vitamin E, and phosphatidylcholine have not shown clear beneficial results.90,96,97 Promising results have been recently obtained with renin-angiotensin system inhibitors, which are known to play an important role in liver fibrogenesis. Administration of candesartan, an angiotensin receptor blocker, to patients with ALD was recently shown to decrease fibrosis.98 To develop new antifibrotic therapies for patients with ALD, there are three critical steps. First, it is important to define the patient population in terms of alcohol consumption. Patients unable to completely stop drinking but likely to be compliant during the clinical trial should be identified. Second, clinical trials should incorporate noninvasive markers of liver fibrosis to monitor the response to therapy because performing paired biopsies in placebo-treated patients is not ethical. And third, antifibrotic drugs that target key pathogenic drivers in ALD should be selected. The ideal antifibrotic drug should be inexpensive, well tolerated for prolonged periods, and not associated with hepatotoxicity or HCC development. Among potential available drugs, the inhibitors of the renin-angiotensin system seem to be the best candidates. Large well-designed clinical trials with this and other targeted therapies should be tested in patients with ALD.

Conclusions and Future Directions In contrast to the remarkable advances in the management of viral hepatitis over the last 30 years, little progress has been made in the diagnosis and management of patients with alcoholic liver fibrosis. To improve this, several critical points should be addressed in the future. • Diagnosis of the early stages of alcoholic liver fibrosis: Alcoholic liver disease is a preventable disease and identi-

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fication of the early stage of ALD (e.g., moderate degree of fibrosis) is of paramount importance to prevent the progression of this disease. There is an urgent need to develop better noninvasive methods and serum markers that allow an accurate assessment of early stage of liver fibrosis without the need of a liver biopsy. Identification of genetic risk factors for alcoholic liver fibrosis: Alcoholic liver disease is the only major liver disease that lacks a whole-genome-wide analysis to identify the main genetic variations that predispose to advanced fibrosis among heavy drinkers. Despite the large number of studies that have assessed the role of genetic variation in susceptibility to ALD, a large-scale, welldesigned, genome-wide association study of factors associated with ALD remains to be performed. More ALD patients should be included in antifibrotic clinical trials: To date, the only affective therapy to attenuate or even reverse fibrosis progression in patients with ALD is continuous alcohol abstinence. The absence of developments on ALD therapy is mainly related to the difficulties of conducting clinical trials in patients with an active alcohol addiction and the lack of interest in this field from drug companies. To develop optimized models of alcoholic liver fibrosis: The current hybrid model of HFD plus intragastric infusion of ethanol with binge ethanol represents a relevant model for alcoholic liver fibrosis. However, this model has limited use owing to its technical difficulty and complexity. Given the fact that chronic-plus-binge ethanol feeding induces more severe liver inflammation and injury than chronic ethanol feeding,99 it is possible to establish a feasible model of alcoholic liver fibrosis by prolonging chronicplus-binge ethanol feeding. To promote translational research from bench to bedside: Despite the extensive research on ALD over the last three decades, the pathogenesis of alcoholic liver fibrosis especially in patients remains obscure. A major initiative created by the National Institute on Alcohol Abuse and Alcoholism in 2012 was to support several large multiinstitutional consortia to conduct translational research on AH.100 Some promising results have been generated from these consortia. We should promote similar translational research for alcoholic fibrosis in the future. To promote interdisciplinary research and collaboration: Abstinence is the best and most important approach for ALD therapy; however, this is difficult to achieve in a large number of patients with active drinking and addiction. Thus, we need to promote interdisciplinary research and collaboration to treat alcoholic liver fibrosis not only with antifibrotic drugs, but also anticraving drugs.

Abbreviations ADH AH ALD ASH

alcohol dehydrogenase alcoholic hepatitis alcoholic liver disease alcoholic steatohepatitis

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Liver Fibrosis in Alcoholic Liver Disease CDT ECM HBV HCC HCV HSC HVPG IL NAFLD NASH PMN PNPLA3 TGFβ1 TIMP-1 TLR

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carbohydrate deficient transferrin extracellular matrix hepatitis B virus hepatocellular carcinoma hepatitis C virus hepatic stellate cell hepatic venous pressure gradient interleukin nonalcoholic fatty liver disease nonalcoholic steatohepatitis; associated molecular pattern polymorphonuclear cell patatin-like phospholipase domain containing protein 3 transforming growth factor β1 tissue inhibitor of metalloproteinases toll-like receptor

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