Epidemiology and Pathogenesis of Alcoholic Liver Disease

Introduction

Alcoholic beverages have been used, and abused, by many cultures since the dawn of time. Whereas some drinking behavior involves symbolic cultural and religion-specific aspects, which effectively limit icts potentially harmful consequences, the pattern of individual drinking varies and is important in determining health or disease. The majority of adult social drinkers enjoy moderate alcohol consumption as a part of a healthy lifestyle, causing no harm to the drinker or society. Moderate drinking, defined in the dietary guidelines in the United States as up to one drink per day for women or two drinks per day for men, normally does not cause liver damage. By contrast, excessive unbridled consumption of alcohol causes health problems to individuals and harm to society. Regarding the liver, chronic heavy drinking consistently results in a continuum of alcoholic liver disease (ALD), which is characterized by a spectrum of histologic lesions ranging from fatty liver (steatosis) in the majority of excessive drinkers to steatohepatitis and fibrosis in approximately 35%, and approximately 10% progress to cirrhosis. Among patients with cirrhosis, approximately 1% to 2% develop hepatocellular carcinoma (HCC). The progression and natural course of ALD depend on the pattern of drinking, and on various aspects including genetic and environmental factors, as well as other comorbid conditions such as viral infections, obesity, and inherited metabolic diseases, as well as diet and medications. In addition, alcoholic hepatitis, a severe form of ALD, can occur in patients with chronic ALD and a history of recent excessive alcohol consumption, and it is associated with high mortality. The necro-inflammatory process associated with alcoholic hepatitis causes rapid progression to fibrosis and cirrhosis in the surviving 40% of cases. This chapter discusses the epidemiology of ALD and focuses on the pathogenesis of ALD.

Epidemiology of Alcoholic Liver Disease

The association between alcohol consumption and liver damage has been known for centuries, and severe liver damage develops in 30% to 40% of heavy drinkers. Liver cirrhosis and HCC are considered to constitute end-stage liver disease (ESLD) and are associated with high mortality. The incidence and prevalence of cirrhosis vary significantly from one region to another, based largely on causative factors. For instance, alcohol abuse, nonalcoholic steatohepatitis, and hepatic C virus (HCV) infection are the leading causes of cirrhosis in the developed world. By contrast, HBV is considered the leading cause in China and Asia. In 2001, cirrhosis was the sixth and ninth most common cause of death among adults in developed and developing countries, respectively, claiming approximately 320,000 lives in developing countries. According to the WHO, approximately 600,000 people die annually due to the acute or chronic consequences of HBV infection, which is endemic in Asia. Globally, HBV- or HCV-attributable cirrhosis accounted for 30% and 27% of cases, respectively; similarly, HCC attributable to HBV or HCV constituted 53% and 25% of cases, respectively. In the European Union alone, the annual death rates are approximately 170,000 and 47,000 from cirrhosis and HCC, respectively. In 2002, approximately 46,700 individuals died from liver cirrhosis and cancer in the USA, whereas in China, approximately 383,000 people die from liver cancer every year.

Epidemiologic studies have suggested a dose-response relationship between the amount of alcohol consumed and the risk of cirrhosis. In France, mortality rates (during 1925-1964) from liver cirrhosis were estimated at 0.014% and 0.357% in individuals who drank less than 80 g (5.7 drinks) and greater than 160 g (11.4 drinks)/day, respectively. More recently, the Dionysos study assessed the prevalence of alcoholic cirrhosis in a general population in northern Italy and reported that the incidence of cirrhosis was higher in subjects who consumed greater than or equal to 30 g/day (2.2%) compared with abstainers (0.08%), whereas those who consumed more than 120 g/day (>8.5 drinks/day) had a cirrhosis prevalence of 13.5%. A meta-analysis published in 1998 showed that consuming greater than 25 g/day increased the relative risk of cirrhosis. Globally, it was estimated that 14,000 women and 66,000 men died from alcohol-induced HCC in 2010. In recent years, a decrease in cirrhosis mortality in most countries of the world was attributed to reductions in alcohol consumption and hepatitis B and C virus infections. In Denmark, between 2006 and 2011, the overall ALD incidence decreased from 343 to 311 per million population per year due to a decrease in per capita alcohol consumption. Conversely, in Hungary and other Eastern European countries, as well as in Ireland and Scotland, high per capita alcohol consumption was accompanied by a marked increase in cirrhosis mortality, with rates in Scotland reaching 42.2 and 20 in 100,000 per year in men and women, respectively. In China, the number of patients with ALD has been rising at an alarming rate over the last 20 years, and ALD has become a leading cause of chronic liver disease.

Ethanol Metabolism

Ingested ethanol (alcohol) is readily absorbed from the gastrointestinal tract, and the rate of absorption is influenced by the amount of alcohol consumed, the rate at which it is consumed, and the prandial state. Alcohol consumed with food is usually absorbed at a slower rate than that consumed on an empty stomach, resulting in a less steep increase in blood alcohol concentration (BAC). BAC is also influenced by body weight, sex, and nonsex genetic factors pertaining to alcohol metabolism, and whether or not the person is a habitual drinker. Only approximately 2% to 10% of the absorbed alcohol is eliminated via the lungs, in the sweat and via the kidneys; the remaining 90% is metabolized mainly via oxidative pathways in the liver and, to a far lesser extent, via nonoxidative pathways in extrahepatic tissues, such as the pancreas. Alcohol metabolism produces 7.1 kcal/g, and as such, it is the preferred fuel in the body.

Oxidative metabolism in the liver is carried out primarily by cytosolic alcohol dehydrogenase (ADH, of which multiple isoenzymes exist) to produce acetaldehyde, a highly reactive molecule that can contribute to liver damage ( Fig. 22-1 ). This oxidation is accompanied by the reduction of NAD ⁺ (nicotinamide adenine dinucleotide) to NADH, thereby generating a highly reduced cytosolic environment in hepatocytes. The cytochrome P450 isozyme CYP2E1, which is present predominantly in the endoplasmic reticulum, also contributes to ethanol oxidation to acetaldehyde in the liver, particularly after chronic ethanol intake. CYP2E1 is induced by chronic ethanol consumption and assumes an important role in metabolizing alcohol to acetaldehyde at elevated alcohol concentrations. In addition, CYP2E1-dependent ethanol oxidation can occur in other tissues in which ADH activity is low. Oxidation of alcohol by CYP2E1 also produces highly reactive oxygen species (ROS), including hydroxyethyl, superoxide anion, and hydroxyl radicals. ROS production is exacerbated by hypoxia and lipopolysaccharide leakage from the gut, which activates Kuppfer cells. Another enzyme, catalase, which is located in the peroxisomes, is capable of oxidizing ethanol in the presence of a hydrogen peroxide (H ₂ O ₂ ) generating system (see Fig. 22-1 ). Alcohol oxidation by catalase is considered a minor pathway of alcohol oxidation.

Acetaldehyde, produced by all of the oxidative pathways, is rapidly metabolized to acetate, primarily by mitochondrial aldehyde dehydrogenase (ALDH2), to form acetate and NADH (see Fig. 22-1 ). Acetate enters the circulation and ultimately is preferentially used as an energy source for the brain, heart, and skeletal muscles. Mitochondrial NADH is oxidized by the electron transport chain, resulting in further augmentation of ROS production. In addition, chronic alcohol consumption depletes glutathione, which protects against ROS, thereby rendering hepatocytes more sensitive to oxidative stress.

The increase in NADH in the cytosol due to ethanol metabolism by ADH results in extensive displacement of the liver's normal metabolic substrates, decreases fat and protein oxidation, and almost completely abolishes carbohydrate metabolism, resulting in hypoglycemia. The process also results in ketoacidosis, which is common in chronically malnourished alcoholics due to the formation of ketone bodies, primarily β-hydroxybutyrate. Heavy alcohol consumption increases the synthesis of triglycerides, resulting in fatty liver and hypertriglyceridemia, and it can exacerbate diabetic hypertriglyceridemia. The increase in the NADH/NAD ⁺ ratio results in an increase in α-glycerophosphate, which favors hepatic triglyceride accumulation and also inhibits mitochondrial β-oxidation of fatty acids. In addition, the increase in NADH increases the ratio of 17-β-hydroxy to 17-keto-steroids, and influences the expression of genes that might play a role in ethanol-induced liver injury. Furthermore, alcohol metabolism diminishes retinoic acid formation and epithelial differentiation, and increases 5-hydroxy-tryptophol.

Several genes pertaining to alcohol-metabolizing enzymes exhibit functional polymorphisms and ethnic variations, which alter the rate of ethanol metabolism, and are associated with susceptibility to addiction, organ damage, and cancer. The most pronounced effect of ethanol-metabolizing gene polymorphism is the ALDH2*2 allele, which has much lower activity than wild-type ALDH2*1. ALDH2 is a tetramer which metabolizes acetaldehyde to acetate, and one defective subunit is sufficient to render the entire enzyme inactive. People who have inactive ALDH2*1/2*2 heterozygotes and inactive ALDH2*2/2*2 homozygotes have 90% and 99% reduced ALDH2 activity, respectively. Approximately 30% to 40% of the East Asian population carry the ALDH2*2 allele, and these individuals exhibit high blood acetaldehyde levels after alcohol consumption and an acetaldehyde-mediated “flushing syndrome,” which includes facial flushing, palpitations, drowsiness, and other unpleasant symptoms. However, many individuals who have inactive ALDH2*1/2*2 heterozygotes nevertheless drink heavily and exhibit high levels of acetaldehyde, even after the intake of only a moderate amount of alcohol. For example, one study reported that individuals who have inactive ALDH2*1/2*2 heterozygotes and consumed even a small amount of ethanol (0.1 g/kg), they exhibited higher peak blood acetaldehyde levels than those who are active ALDH2*1/2*1 homozygotes and consumed a moderate amount of ethanol (0.8 g/kg). Although acetaldehyde has been shown to be toxic to hepatocytes in vitro , the precise in vivo effects of inactive ALDH2-associated acetaldehyde accumulation in ALD are not clear. A recent study reported that ALDH2-deficient mice had a lower degree of steatosis and lower levels of serum ALT but had higher levels of liver inflammation and fibrosis after ethanol and/or carbon tetrachloride administration. Mechanistically, ethanol-fed ALDH2-deficient mice exhibited acetaldehyde and malondialdehyde-acetaldehyde adduct (MAA) accumulation, increased inflammation-associated hepatic interleukin-6 (IL-6) and its downstream signal transducer and activator of transcription 3 (STAT3) activation. Activated STAT3 subsequently promoted alcoholic liver inflammation and fibrosis. The activation of IL-6/STAT3 also played a compensatory role in ameliorating steatosis and hepatocellular damage, resulting in reduced levels of serum ALT in ALDH2-deficient mice following ethanol feeding. Therefore, people with ALDH2 deficiency might not have obvious fatty livers or elevated blood ALT levels after moderate or even heavy drinking, but they might have liver inflammation and fibrosis and should be carefully monitored.

Alcoholic Fatty Liver

Alcoholic fatty liver (steatosis) is the earliest manifestation of heavy drinking and it occurs in approximately 90% of subjects; however, approximately 35% of those with steatosis progress to steatohepatitis (characterized by inflammation and infiltration of polymorphonuclear cells, hepatocyte damage, and formation of Mallory-Denk bodies), and approximately 10% of patients develop cirrhosis. Whereas steatosis is asymptomatic and is usually reversible upon cessation of alcohol consumption, cirrhosis carries a high risk of complications, including ascites, hepatic encephalopathy, variceal bleeding, bacterial infections, and renal failure. Patients with steatosis have been reported to have a lower rate of long-term survival than that of abstinent controls.

While hepatic steatosis is considered a relatively innocuous side effect of heavy drinking, this clinical condition, nonetheless, also develops in situations that involve significant metabolic defects such as obesity, metabolic syndrome, and Type 2 diabetes. Thus, steatosis per se represents metabolic stress that could be a risk factor for the development of more severe forms of liver disease. Both intrahepatic and extrahepatic factors are involved in alcohol-induced steatosis.

Because the liver is the predominant site of ethanol metabolism, steatosis due to heavy alcohol consumption has been attributed to metabolic stress and increase in NADH as described earlier. In addition, the following intrahepatic alcohol effects contribute to steatosis ( Fig. 22-2 ): (1) suppression of mitochondrial fatty acid β-oxidation; (2) enhancement of hepatic uptake of free fatty acids from the circulation; (3) increase in de novo synthesis of fatty acids and triglycerides; and (4) derailment of lipoprotein synthesis and secretion. The ethanol-induced steatosis is further exacerbated by defects in the methionine cycle, resulting in a decrease in glutathione synthesis, a primary line of defense against oxidative stress. In addition, chronic ethanol consumption results in significant changes in the profile of transcription factors that regulate lipid homeostasis in the liver (see Fig. 22-2 ) including: (1) a decrease in peroxisome proliferator-activated receptor (PPAR)-α activity, thereby suppressing the catabolic lipid metabolic pathways, including peroxisomal and mitochondrial fatty acid oxidation; (2) an increase in the activity of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which enhances lipid synthetic pathways; (3) inhibition of the deacetylase sirtuin (SIRT)-1, due to changes in NAD redox state in the liver during ethanol oxidation; and (4) inhibition of the AMP-activated protein kinase (AMPK), followed by elevation of lipid synthesis and down-regulation of fatty acid beta oxidation.

Extrahepatic factors involved in lipid metabolism in the liver, the synthesis and secretion of which are impacted by chronic heavy alcohol consumption, include circulating hormones, cytokines, nutrition and other factors that impinge on the intrahepatic processes leading to steatosis (see Fig. 22-2 ). While cytokines released from Kupffer cells, endothelial cells, or stellate cells are intrahepatic factors, others are dispatched by remote tissues including insulin, adiponectin and leptin (secreted from adipose tissue), and stress hormones and satiety factors that act through the hypothalamus or other brain structures.

Alcoholic Steatohepatitis

Approximately 20% to 40% of heavy drinkers with fatty liver also develop liver inflammation, which is known as alcoholic steatohepatitis (ASH). Several types of inflammatory cells are found in ASH. These include neutrophils, activated Kupffer cells, infiltrating macrophages (IMs), T cells, and natural killer T (NKT) cells, among others, which play complex roles in the pathogenesis of ALD ( Fig. 22-3 ).