Cigarette smoking and alcohol-related liver disease

Abstract

China is a major consumer of alcohol and tobacco. Tobacco and alcohol use are closely linked, with up to 90% of alcoholics having a history of tobacco use, and heavy smokers also tending to be alcoholics. Alcohol-related liver disease (ALD), one of the most common and serious complications of chronic alcohol intake, involving hepatic steatosis, hepatitis, hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC), has become one of the globally prevalent chronic diseases. An increasing number of studies have focused on the association between smoking and ALD and explored the mechanisms involved. Clinical evidence suggests that smoking has a negative impact on the incidence and severity of fatty liver disease, progression of liver fibrosis, development of HCC, prognosis of patients with advanced liver disease, and alcohol-related liver transplant recipients. The underlying mechanisms are complex and involve different pathophysiological pathways, including free radical exposure, endoplasmic reticulum stress, insulin resistance, and oncogenic signaling. This review discusses the deleterious effects of smoking on ALD patients and the possible underlying mechanisms at several levels. It emphasizes the importance of discouraging smoking among ALD patients. Finally, the pathogenic role of electronic cigarettes, which have emerged in recent years, is discussed, calling for an emphasis on social missions for young people.

1. Introduction

Cigarette smoking (CS) is the inhalation of smoke from the burning dried or cured leaves of the tobacco plant, most commonly in the form of cigarettes. Cigarettes undergo a series of chemical reactions of thermal decomposition and thermal synthesis when burned at high temperatures, resulting in the formation of a large number of new substances with complex chemical compositions. Cigarette smoke contains more than 4000 toxic chemicals, including nicotine, and produces addictive stimulant and euphoric properties. Smoke from lit cigarettes consists of two components: particulate matter and the gas phase. Particulate matter, which makes up 8%, refers to the material captured by the filter and contains more than 3500 individual chemical compounds that have been identified, including tar,¹ nicotine,² polycyclic aromatic hydrocarbons,³ heavy metals and others.⁴ The gas phase occupies 92%, referring to the portion of smoke that passes through cigarette filters, and includes large amounts of oxygen and nitrogen harmless gases and some amounts of carbon monoxide and trace amounts of carcinogenic, cancer-promoting, and ciliotoxic substances. The original protein, carbohydrates, vitamins, amino acids and other beneficial substances in tobacco leaves are needed by the human body, once as cigarettes through the combustion of smoke and dust released, will become harmful substances. According to the World Health Organization (WHO), the number of tobacco-related deaths each year exceeds 8 million,⁵ and CS has been identified as one of the major causes of preventable morbidity and mortality worldwide. Conclusive evidence suggests that smoking cessation has beneficial effects, even in cardiovascular events.^6,7 Although the proportion of the population that smokes has declined in most countries, population growth has meant that the total number of smokers remains high and the epidemic of tobacco-related diseases is ongoing.⁸

Chronic alcohol consumption is one of the most common causes of morbidity and mortality worldwide, with an impact on more than 200 disease and injury outcomes.^9,10 WHO defines harmful alcohol consumption as drinking that has detrimental health and social consequences for individuals, their friends and family, and society as a whole (as well as patterns of drinking that are associated with an increased risk of adverse health outcomes), and is responsible for approximately 3.3 million deaths per year (5.9% of all deaths).¹¹ The global proportion of deaths attributable to alcohol is 7.6% for men and 4.0% for women. The liver is the main organ responsible for ethanol metabolism and is therefore particularly sensitive to alcohol intake. Excessive alcohol consumption can lead to liver injury due to metabolites and by-products produced during alcohol metabolism.^12,13 Among them, alcohol-related liver disease (ALD) is one of the most common and serious complications of chronic alcohol intake.¹³ Younger patients, especially middle-aged patients, are more likely to be affected with ALD than other forms of liver disease.¹⁴ ALD encompasses a wide range of disorders, including asymptomatic early ALD (fatty liver or steatosis), steatohepatitis, advanced ALD (alcoholic hepatitis, cirrhosis), and hepatocellular carcinoma (HCC) caused by alcohol consumption.¹⁵ It has a relatively high mortality rate, in part because about 70% of patients are not diagnosed until they develop cirrhosis.¹⁶ The underlying cause of ALD is alcohol consumption, and its progression is largely related to the amount and duration of alcohol intake. More than 90% of patients with alcoholism develop fatty livers, and about 10%–20% of chronic alcoholics develop more severe forms of ALD, such as advanced liver disease and cirrhosis.¹⁷ Individual types of disease progression in ALD can even coexist in the same patient.¹⁸ In addition to alcohol intake, type, and manner of alcohol consumption, there are other factors (e.g., genetic, epigenetic, and environmental factors) involved in the disease progression of ALD.

The probability of severe smoking in alcohol abuse patients is three times that of the general population, and similarly, the rate of alcohol abuse in nicotine-dependent individuals is about four times that of the general population.¹⁹ Alcohol consumption may exacerbate the pathogenic effects on the liver, and heavy smoking can further exacerbate the harmful effects of alcohol abuse, indicating that these factors may have significant synergistic effect.²⁰ Toxic chemicals in cigarettes (e.g., nicotine, tar, carbon monoxide, acrolein, vinyl chloride, arsenic, and cadmium) enter the body’s circulation through the inhalation and metabolize in the liver, causing damage to the liver.²¹ In a prospective cohort study based on 500,000 Chinese adults, long-term smoking was found to be independently associated with a higher risk of death from chronic liver disease, and the risk of disease was reduced by the cessation of smoking.²² A national cohort study from South Korea examined the additional risk of smoking in alcohol drinkers which showed that CS contributes to an increased incidence of ALD, especially in women.²³ Supplemental Table 1 lists the relevant epidemiological studies between CS and ALD in recent years,23, 24, 25 and it is easy to see that CS has become one of the important risk factors for the development of ALD. A growing body of clinical evidence supports the existence of a negative impact of CS on different pathological processes in ALD, with excessive smoking exacerbating the severity of fatty liver, leading to systemic inflammation, oxidative stress, insulin resistance, and resulting in tissue hypoxia and free radical damage,²⁶ and increasing the fibrogenic and carcinogenic effects of alcohol, which negatively impacts liver-related outcomes. This review focuses on the role of CS in ALD disease development, explores possible underlying mechanisms, and emphasizes the importance of prohibiting smoking.

2. Cigarette smoking and alcohol-related fatty liver disease

Excessive alcohol consumption can lead to various liver damages. The first stage is alcohol-related fatty live disease (AFLD), in which a large amount of alcohol leads to fat deposition inside liver cells. This condition may occur in 90% of heavy drinkers, often appearing within 3–7 days after excessive drinking, and is the most common and reversible stage of ALD.^18,27 Increasing evidence suggests that smoking in conjunction with alcohol can induce lipid changes in the liver,28, 29, 30 and may have a negative impact on the incidence and severity of AFLD.

Abnormal lipid metabolism is a key pathological process in the formation of fatty liver,³¹ leading to elevated levels of triglycerides and cholesterol in the serum and liver. Clinical evidence shows that male AFLD patients who smoke have higher levels of total serum cholesterol (TC), low-density lipoprotein (LDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GGT) activity than non-smokers, and lower levels of high-density lipoprotein (HDL), suggesting a synergistic effect of cigarette smoking in the development of AFLD. Among those who smoke and drink, compared to those who only quit drinking, LDL, ALT, AST, and γ-GGT levels are reduced, while HDL levels are increased after quitting smoking and drinking, indicating that smoking cessation is an important therapeutic intervention for AFLD. Animal studies have also found that serum AST levels are elevated in rats in the smoking group, drinking group, and smoking with drinking group, with the group of rats that received both interventions showing more severe damage compared to the intervention group alone.³²

Oxidative stress and lipid peroxidation also promote AFLD formation. CS is the main source of exogenous free radical exposure in humans.³³ Free radicals can damage cellular structures, cell membranes, or large molecules such as proteins, lipids, and nucleic acids.^34,35 This process is called “oxidation”, and the induced damage is called “oxidative damage”. Cigarette smoke is rich in free radicals, including reactive oxygen species (ROS), reactive nitrogen species (RNS), and carbon-centered free radicals, with 10¹⁷ oxidant molecules in each puff of smoke. Oxidative stress is one of the main mechanisms of toxicity caused by smoke exposure, and systemic oxidative stress caused by smoke exposure can lead to liver oxidative damage. In rats that smoke and consume alcohol, oxidative stress indicators of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity levels decreased in liver tissue, while the oxidant malondialdehyde (MDA) content increased. Animal experiments have shown that cigarette smoke,³⁶ toxic components in smoke such as nicotine and amine formate ethyl play a role in this process.^37,38

Cytochrome P450 (CYP) is the main metabolic enzyme in the body. The interaction of cigarette smoke and alcohol intake affects hepatic cytochrome.³⁹ Long-term excessive alcohol consumption leads to the oxidation of ethanol to acetaldehyde by CYP2E1, resulting in the overproduction of free radicals and ROS, triggering an oxidative stress response.^40,41 Multiple studies have indicated that tobacco smoke and ethanol may induce CYP2E1, potentially contributing to the synergistic increase in the risk of alcohol-induced liver disease development.^42,43 Both cigarette smoke and ethanol can induce CYP2E1, which metabolizes ethanol in the body to produce free radicals, promoting lipid peroxidation. CYP2A5 is the main enzyme responsible for the metabolism of nicotine and cotinine in mice, and the ROS produced by the metabolism of nicotine by CYP2A5 is associated with enhanced AFLD.³⁷ Studies have found that nicotine and cotinine promote the progression of AFLD in wild-type mice, but have no effect on CYP2A5 gene knockout mice.⁴⁴ During the CYP2A5-dependent metabolism of nicotine and cotinine, the final product of lipid peroxidation, 4-hydroxynonenal (HNE), increases, thereby increasing P21 encoded by the Cdkn 1a gene. P21 inhibits cell proliferation, leading to damage to hepatic cell proliferation. When ethanol is used in combination with nicotine or cotinine, it greatly increases the P21 levels in wild-type mice compared to ethanol used alone. This suggests that the enhanced AFLD by nicotine and cotinine is related to the ROS-HNE-P21 pathway inhibiting liver proliferation.

Research has found that the molecular mechanisms of AFLD include ethanol activation of sterol regulatory element binding protein-1 (SREBP-1), inducing a series of fat-synthesizing enzymes, and stimulating fat production.⁴⁵ Similarly, vinyl chloride, a harmful substance found in cigarette smoke, has been shown to induce liver steatosis in mice.⁴⁶ Once inhaled into the body, vinyl chloride is metabolized and activated by CYP2E1, triggering liver oxidative stress and endoplasmic reticulum stress, thereby upregulating the expression of SREBP-1 and its target genes, including genes related to de novo lipogenesis such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), leading to the increased expression of mRNA and protein, resulting in increased lipid synthesis within the liver cells, inducing hepatic lipid accumulation, and promoting the occurrence and development of fatty liver in mice.⁴⁷

Finally, ethanol feeding selectively regulates the induction of endocannabinoid 2-arachidonoylglycerol (2-AG) in hepatic stellate cells (HSCs), activating hepatic cannabinoid-1 (CB1) receptor paracrine signaling to mediate ethanol-induced steatosis.²⁸ An important role for the endocannabinoid system in the modulation of the addictive properties of nicotine has been clearly established.⁴⁸ Nicotine may enhance ethanol-induced fatty liver through intercellular interactions, specifically by activating HSCs to secrete 2-AG, promoting intrahepatic lipid accumulation and activating hepatic CB1 receptor to induce hepatocellular lipid deposition (Fig. 1).

Fig. 1.

Cigarette smoking and alcohol-related fatty live disease. Cigarette smoke induces the expression of CYP2E1, leading to the generation of ROS. The abundant free radicals generated cause oxidative damage. Vinyl chloride up-regulates the expression of SREBP-1, resulting in increased fat accumulation. Nicotine inhibits hepatic intelligence through the HNE-P21 pathway and stimulates hepatocyte secretion of 2-AG, promoting fat accumulation. Abbreviations: 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid-1; GSH-PX, glutathione peroxidase; HNE, 4-hydroxynonenal; HSC, hepatic stellate cell; MDA, malondialdehyde; ROS, reactive oxygen species; SOD, superoxide dismutase; SREBP-1, sterol regulatory element binding protein-1. Image created with BioRender. com, with permission.

3. Cigarette smoking and alcohol-related hepatitis

Alcohol-related hepatitis (AH) is the result of further damage to AFLD, developing in 10%–35% of heavy drinkers,¹⁵ and is a destructive acute ALD with a high short-term risk of death.⁴⁹ The “two-hit” hypothesis revolves around oxidative stress and lipid peroxidation as core concepts, where the initial hit leads to the formation of fatty liver, and the second hit is mediated by lipopolysaccharide (LPS)-induced low-grade intestinal endotoxemia (IETM), resulting in inflammation, necrosis, and fibrosis of the fatty liver. Animal studies have shown that exposure to CS can exacerbate liver inflammation. CS exposure has varying degrees of impact on the liver tissue structure in rats, as observed in hematoxylin and eosin (HE) staining, indicating that CS exposure can exacerbate the inflammatory response in rat liver tissue. Additionally, the inflammatory response and sinusoidal congestion of the liver show a dose-dependent relationship with the duration and dosage of cigarette smoke exposure.⁵⁰ Similarly, mammalian tree shrews also demonstrate comparable results, as HE staining reveals liver cell inflammation and necrosis induced by exposure to cigarette smoke.⁵¹

CS affects systemic inflammation by activating and releasing inflammatory cells into the circulation and increasing circulating inflammatory mediators (including acute phase proteins and pro-inflammatory cytokines) leading to hepatocellular injury.⁵² In vivo studies in animals have found that serum and liver tissue levels of interleukin (IL)-1, IL-6, tumour necrosis factor-alpha (TNF-α) levels after smoking were higher than those of the control group. The hallmark of systemic inflammatory response is the stimulation of the hematopoietic system, particularly the bone marrow, leading to the release of white blood cells (WBCs) and platelets into circulation. Studies have shown that prolonged CS increases total WBC count, primarily due to an increase in circulating polymorphonuclear neutrophils (PMN).⁵³ One of the possible molecular mechanisms by which CS induces the activation of inflammatory cells is the nuclear factor kappa B (NF-κB) pathway.⁵⁴ CS contains peroxide components, which, upon entering the blood, activates systemic NF-κB, leading to increased gene expression of inflammatory factors such as TNF-α, IL-6, and IL-8 after NF-κB enters the cell nucleus, generating a cascade amplification effect of inflammatory reaction, enhancing systemic inflammatory response. Meanwhile, the positive feedback loop between NF-κB and TNF-α seems to exacerbate the level of inflammation and liver cell damage.⁵⁵ Several studies have shown that fibrosis development can be prevented and liver inflammation alleviated by inhibiting the NF-κB signaling pathway.56, 57, 58 In human experiments, it has been found that peripheral blood NF-κB and its inhibitory protein I-κB, IL-6 mRNA, and IL-8 concentration in cell supernatant are all higher in healthy smokers than non-smokers. After stimulation with very low concentrations of LPS, these indicators did not show significant changes in non-smokers, while they significantly increased in smokers. These results suggest that CS increases the body’s sensitivity to bacterial infections.

Finally, research has shown that cigarette smoke can impair insulin/insulin-like growth factor (IGF) signaling, mediating liver damage and steatohepatitis.⁵⁹ The metabolite of nicotine-derived nitrosamine ketone (NNK), plays a major role in this pathway.⁶⁰ NNK is toxic and degenerative to the liver, causing steatohepatitis, insulin resistance, DNA damage, lipid peroxidation, activation of pro-inflammatory cytokines, and accumulation of hepatic ceramides, exacerbating the severity of ALD.⁶¹ Long-term alcohol abuse and low-dose exposure to NNK have a certain impact on insulin/IGF-1 signaling mediators in the liver, leading to significant impairment of insulin signal transduction in a model of chronic alcoholic steatohepatitis and in patients with ALD.^62,63 The research results from the study of animal internal environment showed that NNK (with or without ethanol) decreased the relative phosphorylation levels of IGF-1, glycogen synthase kinase 3β (GSK-3β), and Akt. The expression of insulin receptor gradually decreased in the liver exposed to NNK and/or ethanol,⁶¹ indicating that both ethanol and NNK can cause damage to insulin/IGF-1 signal transduction in the liver. Moreover, exposure to NNK and ethanol resulted in a significant increase in the levels of triglycerides and cholesterol in the liver tissue, as well as a large number of inflammatory factors such as interferon-gamma (IFN-γ), IL-13, increased lipid droplets and collagen fiber abundance, significantly reduced and altered mitochondria, increased DNA adduct O6-methylguanine, suggesting that NNK exposure can lead to liver damage, induce steatohepatitis, possibly mediated by NNK metabolism and DNA adduct formation in the liver (Fig. 2).^64,65

Fig. 2.

Cigarette smoking and alcohol-related hepatitis. NNK in cigarette smoke mediate liver injury and steatohepatitis by impairing insulin/insulin-like growth factor signaling. Peroxide components enter the bloodstream and activate the systemic nuclear transcription factor NF-κB, which enters the nucleus and causes the elevation of inflammatory factors, creating a cascade amplification of the inflammatory response. Abbreviations: GSK-3β, glycogen synthase kinase 3beta; IFN-γ, interferon-gamma; IGF-1, insulin-like growth factor 1; IL, interleukin; NF-κB, nuclear factor kappa B; NNK, nicotine-derived nitrosamine ketone; pAkt, phosphorylated protein kinase B; TNF-α, tumor necrosis factor-alpha. Image created with BioRender. com, with permission.

4. Cigarette smoking and alcohol-related hepatic fibrosis

As the vicious cycle continues (i.e. liver injury and regeneration), acetaldehyde-protein adducts inactivate DNA repair, damage hepatic mitochondria, impair oxygen utilization, and further stimulate collagen band synthesis and deposition between the central vein and portal vein areas, leading to alcohol-related hepatic fibrosis.^15,66 Hepatic fibrosis is the injury-repair response of the liver to various chronic liver injuries, characterized by the accumulation of excess collagen and other extracellular matrix (ECM) proteins. CS is an independent risk factor for advanced stages of liver fibrosis.^24,67

Animal studies have found that the content of hydroxyproline (Hyp) in the livers of rats exposed to smoking and alcohol consumption for 12 weeks is significantly higher than in the groups exposed to only smoking or only alcohol consumption. Hyp is an important product of collagen metabolism, a unique amino acid derived from collagen molecules in connective tissue. The content of Hyp in liver tissue can serve as a characteristic biochemical marker reflecting the degree and progression of liver fibrosis.⁶⁸ Therefore, it is speculated that smoking and alcohol consumption may synergistically promote the development of liver fibrosis, and the coexistence of these two lifestyle habits seems to explain the difference in the progression speed of fibrosis among patients with similar degrees of alcohol abuse.

CS stimulates the release of transforming growth factor-beta (TGF-β) and the activation and proliferation of resident fibroblasts. In vivo studies have found that simultaneous injection of the major component of tobacco smoke, nicotine, during ethanol feeding in mice increases liver collagen I deposition and fat accumulation, and HSC activation is accelerated with combined exposure to nicotine and ethanol.⁶⁹ HSC can express nicotinic acetylcholine receptor (nAChR),⁷⁰ and nicotine induces HSC proliferation and the expression of collagen I and TGF-β. Therefore, nicotine may directly activate HSC by binding to nAChR, promoting hepatic collagen I deposition and fibrosis. In addition, smoking-induced liver damage also activates HSC proliferation, whereby damaged hepatic parenchymal cells release ROS, promote inflammatory response, stimulate cell apoptosis, activate HSC, enhance TGF-β secretion, and collagen synthesis, thereby forming ECM deposition and late-stage fibrosis.^71,72 Another study found that after exposure to CS, the levels of SOD and GSH-PX activity in the liver of rats decreased, while the MDA content increased. Additionally, the levels of serum AST, ALT, and the four indicators of liver fibrosis (including hyaluronic acid, laminin, collagen IV, and procollagen III) all increased. The expression of TGF-β1 and alpha-smooth muscle actin (α-SMA) within the liver also increased, suggesting that smoking-mediated oxidative stress may contribute to liver fibrosis by activating HSC.

Exercise science can lead to changes in the microvascular system, such as endothelial dysfunction, smooth muscle cell proliferation, and vasoconstriction, resulting in impaired nitric oxide delivery and tissue hypoxia.73, 74, 75 Under hypoxic conditions in the liver, increased expression of vascular endothelial growth factor (VEGF) and collagen I in activated hepatic stellate cells (aHSC) promotes the development of fibrosis.75, 76, 77

CS can induce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, impair glutathione and other antioxidant pathways, reduce antioxidant defense ability, and induce oxidative stress, leading to the generation of reactive oxygen species and lipid peroxidation, further resulting in hepatocyte inflammation, cell damage, HSC activation, leading to the proliferation of fibrotic mediators, matrix metalloproteinases, and ECM proteins.²⁴

Iron deposition may promote the progression of liver fibrosis in chronic smokers, and the indirect toxic effect of smoking may exacerbate iron deposition. The indirect toxic effect of smoking is secondary polycythemia, which is an increase in carbon monoxide and a decrease in oxygen-carrying capacity of red blood cells, leading to tissue hypoxia, increased erythropoietin production, and subsequent bone marrow proliferation.⁷⁸ Subsequently, due to increased red blood cell destruction, iron breakdown and metabolism increase, leading to higher erythropoietin levels, stimulating more iron absorption in the intestines, thus promoting iron deposition. Iron is cleared by macrophages and ultimately accumulates in liver cells, promoting oxidative stress and liver damage, furthering the progression of liver fibrosis. Additionally, excess iron can synergize with alcohol, inducing oxidative stress and lipid peroxidation.^15,79

CS is associated with the impairment of intestinal barrier, increased permeability, and bacterial translocation.⁸⁰ A two-sample Mendelian randomization study hints at the hazards of tobacco use on gut microbiota dysregulation and clarifies the potential role of specific gut microbiota on smoking behavior.⁸¹ In vivo studies have shown intestinal nicotine accumulation in mice after receiving cigarette smoke exposure.⁸² Toll-like receptor 4 (TLR4) on the surface of HSCs is activated by LPS from intestinal bacteria, leading to cell activation and fibrosis, which is a key pathway in promoting fibrosis in ALD.^75,83,84 This mechanism links fibrosis to the microbiome and emphasizes the role of the gut-liver axis in the development of ALD. The gastrointestinal microbiome is a complex ecosystem of 10–100 trillion microorganisms, most of which are bacteria in the gut and develop immediately after birth. Its diversity or composition may be influenced by host physiology and environmental factors. Among these, alcohol and smoking are potential modulators of the gastric microbiota. In vivo, animal studies suggest that CS exacerbates inflammatory damage in a rat model of colitis.⁸⁵ It is noteworthy that gut flora are important scavengers of potentially toxic compounds. An in-depth study of the role of gut flora in CS-promoted ALD is important for new drug development and clinical patient care (Fig. 3).

Fig. 3.

Cigarette smoking and alcohol-related hepatic fibrosis. Cigarette smoke induces the NADPH system leading to ROS production and lipid peroxidation, exacerbates oxidative stress by promoting iron deposition, and activates HSC by activating TLR4 via the gut-liver axis. Nicotine induces HSC proliferation and promotes collagen deposition via nAChR. Abbreviations: aHSC, activated hepatic stellate cells; α-SMA, alpha-smooth muscle actin; ECM, extracellular matrix; HA, hyaluronic acid; IV.C, collagen IV; LN, laminin; LPS, lipopolysaccharides; nAChR, nicotinic acetylcholine receptor; NADPH, nicotinamide adenine dinucleotide phosphate; PCⅢ, procollagen III; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TLR4, Toll-like receptor 4; VEGF, vascular endothelial growth factor. Image created with BioRender. com, with permission.

5. Cigarette smoking and alcohol-related cirrhosis

The continued formation of scars in the liver and the spread of collagen throughout the liver (i.e. bridging fibrosis) can lead to alcohol-related cirrhosis (AC).⁸⁶ Cirrhosis and its complications are significant health issues and can, in some cases, even lead to HCC. Smoking is very common in AC (60%–78%) and leads to increased mortality if not stopped.⁸⁷ The 5-year survival rates for smokers and non-smokers under the age of 55 are 42% and 73% respectively, and are 17% and 43% respectively for over the age of 55.⁸⁸

Clinical evidence shows that CS is associated with the risk of AC. Studies have found that the interaction between the polymorphism of the N-acetyltransferase 2 gene and environmental factors such as CS can increase the susceptibility of long-term drinkers to AC. The proportion of rapid acetylation genotypes and smoking population developing alcoholic cirrhosis is higher than that of non-smokers (P = 0.002), with a 2.45-fold increase in the risk of cirrhosis.⁸⁹ A study including 128,934 women and men found that the risk of AC increased threefold in daily smokers of one pack or more compared to lifelong non-smokers, and the risk was higher in smoking women than men,⁹⁰ consistent with the results of a large-scale population study with long-term follow-up in Denmark.⁸⁷ At the same time, several epidemiological studies have shown that the combined effect of CS and alcohol consumption increases the risk of developing cirrhosis and mortality.^91,92

Although there is substantial clinical evidence supporting a link between CS and AC, there is limited research on the mechanism pathways through which CS affects AC, necessitating more in vivo and in vitro studies to elucidate the underlying mechanism.

6. Cigarette smoking and alcohol-related hepatocellular carcinoma

The carcinogenic effects of alcohol can be triggered by acetaldehyde and ROS, promoting mutagenesis and interfering with DNA methylation, synthesis and repair, which in turn leads to alcohol-related hepatocellular carcinoma (aHCC).⁹³ The annual incidence of aHCC in patients with cirrhosis has been reported to range from 0.32% to 5.60%.⁹⁴ In terms of mortality, alcohol is responsible for 19% of all liver cancer deaths globally, and is the second fastest growing cause of age-standardized liver cancer mortality.⁹⁵ CS has a synergistic effect in increasing the risk of HCC in ALD patients.⁹⁶

The International Agency for Research on Cancer (IARC) has identified both tobacco and alcohol as Group I human carcinogens causing liver cancer as early as the beginning of the 21st century. Various components of tobacco smoke, such as nicotine, NNK, the polycyclic aromatic benzopyrene, and heavy metals (arsenic, cadmium), have been shown to be carcinogenic. CS and alcohol consumption may increase the risk of cancer development through shared or cumulative hepatocarcinogenic pathways.⁷⁵ For example, the enzyme CYP2E1 activates the pro-carcinogenic components of tobacco smoke (nitrosamines and benzene), and is also an important pathway in the metabolism of alcohol. Another example is that alcohol consumption may be one of the factors influencing the distribution and retention of arsenic from tobacco smoke in human tissues. On the one hand, it may promote the uptake of inorganic arsenic by altering and disrupting the molecular composition of cell membranes, and on the other hand, it may affect the distribution and retention of inorganic arsenic in tissues by altering the methylation of inorganic arsenic, which may contribute to cancer progression. In addition, alcohol can act as a solvent for tobacco carcinogens, which may partly explain their synergistic effect on cancer.⁹⁶

For patients with chronic liver disease, early cessation of smoking reduces the risk of developing HCC.⁹⁷ Data support that smoking cessation is negatively associated with the risk of HCC, with those who quit more than 20 years ago having nearly the same risk of developing the disease as never-smokers.⁹⁸

7. Impact of smoking on ALD liver transplant recipients

ALD is a major indication for liver transplantation (LT) globally.⁹⁹ What’s more, early LT must always be considered in selected patients with severe AH regardless of their abstinence status.¹⁰⁰ Smoking is prevalent among ALD patients undergoing LT evaluation, and most ALD recipients who smoked before transplantation quickly return to addictive levels of smoking after LT.¹⁰¹ A systematic review and Meta-analysis of all published studies up to 2018 suggested that CS is one of the important risk factors for disease recurrence after LT.¹⁰² It has been proven that CS has a negative impact on LT outcomes,⁷⁵ delaying wound healing and significantly increasing vascular complications, especially arterial events. Among the complications associated with CS, three main factors need to be highlighted: (i) increased risk of vascular complications,^103,104 such as hepatic artery thrombosis; (ii) development of new tumors,^104,105 including intrahepatic and extrahepatic cholangiocarcinoma; (iii) increased non-transplant related mortality,¹⁰⁶ mainly due to cardiovascular events. Multifactorial analysis indicates that cardiovascular events and malignancies mainly occur in ALD liver transplant recipients.¹⁰⁷

The guidelines on Liver Transplantation for Alcoholic Liver Disease, compiled by the International Liver Transplantation Society, strongly recommend promoting smoking cessation in alcohol-related liver transplant recipients to improve overall health and patient prognosis.¹⁰⁷ Smoking cessation is an important goal in the post-transplant care of ALD patients. Many liver transplant programs and health insurance plans do not provide/cover liver transplants for patients currently smoking.⁷⁵ Patients who quit smoking for at least two months before LT have a significantly reduced risk of vascular complications,⁷⁵ so medical assistance should be provided to promote smoking cessation before listing patients for LT.

8. Potential harm of e-cigarettes

E-cigarettes are battery-powered inhalation devices that resemble cigarettes and heat a solution containing psychoactive compounds (usually nicotine or tetrahydrocannabinol) as well as flavors and other additives to deliver vapor to the user.¹⁰⁸ The use of e-cigarette devices is rapidly gaining popularity among young people. A systematic review and Meta-analysis involving 17,389 adolescents and young adults found that those who use e-cigarettes (containing nicotine) may become addicted to nicotine, and the use of e-cigarettes is associated with an increased likelihood of subsequent smoking among adolescents.¹⁰⁹ The use of e-cigarettes is a significant risk factor for smoking among adolescents and young adults, and the misconception that e-cigarettes can replace smoking and are therefore healthier may be a key factor.

Like traditional cigarettes, e-cigarettes contain a variety of substances that have potential harmful effects on human health. Clinical evidence shows that using e-cigarettes can lead to liver damage, with clinical manifestations such as abdominal pain and elevated liver enzymes.^110,111 Exposure to e-cigarettes can even induce liver steatosis in adult offspring mice when the maternal mice are exposed to them.¹¹² The aerosol and ingredients of e-cigarettes may induce liver injury through different mechanisms. Consistent with direct exposure to cigarette smoke, repeated exposure to e-cigarettes increased CYP2A5 levels and ROS production.¹¹³ Interestingly, unlike traditional smoking, the harmful effect of e-cigarettes on liver steatosis is related to oxidative stress, independent of the AMPK signal.¹¹⁴ Other mechanisms such as direct DNA damage and mitochondrial dysfunction have also been suggested to play a role.¹¹⁵ Furthermore, flavoring chemicals used in e-cigarettes can independently cause liver cell injury apart from the aerosol and nicotine.¹¹⁶ Finally, there is evidence supporting that the use of e-cigarettes can induce endothelial dysfunction and trigger cardiovascular diseases.^117,118 It is well known that endothelial dysfunction is a key event involving the interaction between liver injury, fibrosis progression, and hemodynamic disturbances.¹¹⁹ Therefore, toxic compounds in e-cigarettes leading to liver endothelial injury may significantly promote the progression of liver damage.

But currently, there is a lack of research linking e-cigarettes with ALD, and more evidence from in vivo and in vitro studies as well as clinical research is needed to reveal the connection between the two and the mechanisms involved.

9. Conclusions and future prospects

The use of alcohol and tobacco is closely related, as reports show that up to 90% of alcoholics smoke, and heavy smokers are often alcoholics. Additionally, 90% of patients with alcoholic liver disease are also smokers. Long-term heavy drinkers often have a low smoking cessation rate, which may be related to the increased nicotine metabolism in drinkers.¹²⁰ There is a growing body of clinical evidence and in vivo studies confirming the negative impact of cigarette smoke exposure on the incidence and severity of fatty liver disease, progression of liver fibrosis, development of HCC, prognosis of patients with advanced liver disease, and alcohol-related liver transplant recipients (Fig. 4).

Fig. 4.

Cigarette smoking and alcohol-related liver disease. The impact of cigarette smoking on the development and progression of alcohol-related hepatic steatosis, inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Abbreviations: 2-AG, 2-arachidonoylglycerol; HSC, hepatic stellate cell; IGF, insulin-like growth factor; IL, interleukin; NADPH, nicotinamide adenine dinucleotide phosphate; SREBP-1, sterol regulatory element binding protein-1; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha. Image created with BioRender. com, with permission.

This review explores the potential impact of CS on different pathological processes of ALD, discusses possible mechanisms, and emphasizes the necessity of smoking cessation for patients with ALD. The oxidative stress induced by CS and the depletion of glutathione during ethanol metabolism synergistically elevate the overall oxidative stress level in the liver, leading to lipid peroxidation. Oxidative stress is a crucial mechanism underlying liver injury and is a central aspect of the pathogenesis of ALD. Additionally, cigarette smoke and alcohol intake interactively affect liver CYP450. CS also increases the production of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-8, while reducing the levels of anti-inflammatory cytokines. Moreover, heavy smoking can cause necrotizing inflammation, cell apoptosis, and excessive iron deposition in the liver. CS also damages the liver through mitochondrial injury, endoplasmic reticulum stress, and insulin resistance, thereby enhancing alcohol-induced liver injury. The components of cigarette smoke are numerous, and the pathogenesis of ALD is complex. Further research is needed to delve into the signaling pathways through which smoking influences ALD. Furthermore, e-cigarettes have rapidly gained popularity among adolescents and have become a significant health risk factor. However, there is a lack of effective research on the connection and potential mechanisms between e-cigarettes and ALD. Lastly, due to the harmful effects of cigarette smoke on the liver transplant of ALD patients, efforts should be made to promote smoking cessation in alcoholic liver transplant recipient.

The adverse effects of dual use of tobacco smoke and alcohol on the liver have been recognized and greater emphasis has been placed on exploring the link between the two, but translating this mechanistic enquiry into therapeutic potential will require addressing numerous challenges, including the limited research currently available into the pathogenesis of ALD. Nevertheless, these efforts are expected to provide innovative and effective therapeutic interventions for patients with ALD combined with tobacco use, providing targets and ideas for new drug development.

Authors’ contributions

Hui-Min Lin and Jing-Rong Zhang contributed equally to this work and should be considered co-first authors. Hui-Min Lin: Writing – original draft, Data curation, Conceptualization. Jing-Rong Zhang: Writing – original draft, Visualization. Meng-Xue Li: Investigation. Hui Hou: Supervision. Hua Wang: Supervision. Yan Huang: Writing – review & editing, Funding acquisition. All authors have read and approved the final version of the manuscript.

Declaration of competing interest

Hua Wang is an editorial board member for Liver Research and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.

Appendix A. Supplementary data

The following is the Supplementary data to this article: