Beer And Hep B: Is There A Link?

Alcohol abuse is a major health problem worldwide and is a leading cause of cirrhosis, which is linked to an increased risk of liver cancer. Excessive alcohol use may also directly cause liver cancer. Persons with chronic hepatitis B or C infections who overuse alcohol have an even higher risk of developing liver cancer.

Alcohol abuse is a high-risk factor for the accelerated progression of chronic hepatitis B into more severe liver diseases such as cirrhosis and hepatocellular carcinoma

Alcohol abuse is a high-risk factor for the accelerated progression of chronic hepatitis B into more severe liver diseases, such as cirrhosis and hepatocellular carcinoma. Hepatitis B is a viral infection that affects the liver and can cause inflammation and necrosis of hepatocytes. Alcohol abuse can cause rapid progression of liver disease in hepatitis B-infected patients and allow the virus to persist chronically.

Alcohol metabolism in the liver can lead to an increase in the production of reactive oxygen species, which can cause oxidative stress and lipid peroxidation. This, in turn, can lead to cell death, tumorigenesis, altered cell-to-cell communication, and increased susceptibility to viral infections. Alcohol abuse can also impair the immune system, making it less effective at fighting off the hepatitis B virus.

Chronic alcohol intake can alter the architecture and compromise the functional capacity of the liver. It can also increase the levels of hepatitis B markers, such as hepatitis B surface antigen and viral DNA, in the blood. This can lead to a higher frequency of hepatitis B markers in alcoholics and increase the risk of developing cirrhosis and hepatocellular carcinoma.

In addition, alcohol abuse can increase the risk of fibrosis in patients with hepatitis B and enhance liver necroinflammatory changes. It can also lead to an increased alteration of liver tests and self-resolved hepatitis B infection can be a risk factor for developing hepatocellular carcinoma in patients with alcoholic cirrhosis.

Overall, alcohol abuse is a significant risk factor for the progression of chronic hepatitis B to more severe liver diseases, such as cirrhosis and hepatocellular carcinoma. The combination of hepatitis B infection and alcohol abuse can have detrimental consequences, and a better understanding of the mechanisms behind this interaction is needed to develop effective treatments and prevent liver disease progression.

Alcohol can increase the replication of hepatitis B virus, oxidative stress, and cytotoxicity but decrease antiviral immune responses in the liver

Alcohol can increase the replication of the hepatitis B virus, oxidative stress, and cytotoxicity but decrease antiviral immune responses in the liver.

Alcohol abuse is a major health problem, with 15.1 million adults and 623,000 adolescents in the US suffering from alcohol use disorders. Alcohol abuse is also linked to an increased risk of developing end-stage liver disease, cirrhosis, and hepatocellular carcinoma.

The liver is the main site for the replication of hepatotropic viruses such as hepatitis B and C, and is also the primary site of ethanol metabolism. Alcohol metabolism is catalysed by alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is the main metabolite responsible for the majority of the toxic effects associated with alcohol use.

The effects of alcohol on the replication of hepatitis B and C are not fully understood. However, studies have shown that alcohol can increase the replication of hepatitis B and possibly C, as well as their host hepatocytes. Alcohol can also suppress the antiviral immune response, increase oxidative stress, and induce endoplasmic reticulum and Golgi apparatus stress.

The combination of hepatitis B infection and alcohol abuse can have detrimental consequences, including the development of end-stage liver diseases.

Alcohol abuse is correlated with an increased risk of developing end-stage liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B

The hepatitis B virus (HBV) and alcohol abuse are both major causes of end-stage liver disease. Alcohol abuse not only causes the rapid progression of liver disease in HBV-infected patients but also allows HBV to persist chronically. The mechanisms by which alcohol promotes the progression of HBV-associated liver disease are not fully understood, but potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication.

The risk of developing cirrhosis and HCC is increased in patients with chronic HBV infection and heavy alcohol consumption. In a prospective cohort study in Japan that followed 610 consecutive HBsAg-positive patients for a median observation period of 4.1 years, cumulative alcohol consumption ≥ 500 kg was independently associated with the carcinogenesis rate, with a relative risk of 8.37.

In a retrospective cohort study of 966 cirrhotic patients in Taiwan, with a mean follow-up period of 2.9-5.2 years, the annual incidence of HCC was significantly higher in 632 cirrhotic patients with HBV infection and heavy alcohol consumption (≥ 80 g/d for ≥ 5 years) than in 132 patients with HBV infection alone (9.9% and 4.1%, respectively).

In a prospective cohort study in Korea that followed 4495 HBsAg-positive and 433239 HBsAg-negative men for a median observation of 10 years, moderate alcohol consumption (≥ 25 g of ethanol per d) raised the relative risk of mortality from HCC to 1.13 in HBsAg-positive men but was not significant.

In a large-scale, prospective cohort REVEAL-HBV study in Taiwan, which included more than 3500 patients (aged 30-65 years), a regression analysis revealed that male sex, older age, seropositivity for HBeAg, and habitual alcohol consumption are significantly associated with the development of HCC. The adjusted hazard ratio (with 95% confidence interval) for HCC was 1.6 (1.1-2.4) for habitual alcohol consumption, defined as drinking alcohol ≥ 4 days per week for ≥ 1 year.

In a case-control study in Italy that investigated the dose-effect relationship between alcohol consumption and HCC, separately, in men and women, a steady linear increase in the odds ratio of HCC with increasing alcohol intake, for values of > 60 g/d in both sexes was found. In addition, a synergism between alcohol drinking and chronic HBV infection was found, with the odds ratio of 2.13 in HBsAg-positive drinkers consuming > 60 g per day, compared to HBsAg-positive nondrinkers or drinkers of ≤ 60 g/d.

The combination of alcohol and hepatitis B virus can lead to more severe liver damage

Alcohol abuse is a major health problem worldwide. Alcohol abuse not only causes rapid progression of liver disease in hepatitis B virus (HBV)-infected patients but also allows HBV to persist chronically. The combination of HBV infection and alcohol abuse enhances liver injury progression, especially to hepatocellular carcinoma (HCC), which is the fifth most common cancer type and the second leading cause of cancer death worldwide. The mechanisms underlying these detrimental effects of alcohol in HBV-infected patients are not fully understood and are less clear than with chronic hepatitis C virus (HCV) infection.

The possible mechanisms for the chronic liver diseases induced by the combination of alcohol and HBV infection are increased HBV replication, oxidative stress, cell organelles stress (such as endoplasmic reticulum and Golgi stress) and, importantly, weakened immune responses.

The natural history of HBV has been subdivided into two types of infection. In adults, 90%-95% of HBV infections is acute, where immune-competent people clear the viral infection effectively. Acute infection is characterised by inflammation and necrosis of hepatocytes and has a low mortality rate (0.5%-1%). The persistence of HBsAg in blood for longer than 6 months after the initial infection is a sign of chronic hepatitis B. This infection is mainly asymptomatic without any intense liver damage, but in some cases, it leads to chronic hepatitis, followed by fibrosis, cirrhosis development, and HCC.

The progression to chronic hepatitis B infection enhances the risk for the development of end-stage liver diseases leading to increased mortality. The hepatic steatosis induced by HBV infection is mainly caused by the HBx protein by increasing the mitochondrial reactive oxygen species (ROS) levels, oxidative stress and through the interaction with liver-enriched transcription factors, hepatocyte nuclear factor 3-β, CCAAT/enhancer-binding protein α, peroxisome proliferator-activated receptor α axis, and fatty acid–binding protein 1. Interaction between viral proteins in the liver and the immune system induces hepatocyte damage, followed by tissue repair. This repair process causes deposition of extracellular matrix leading to progressive liver fibrosis. HBV X protein may also have fibrogenic and oncogenic effects on the liver. Progression to advanced fibrosis can be either rapid or slow, or sporadic based on disease stages and levels of liver inflammation and injury. A recent study reported that elevated α-fetoprotein levels and hepatitis B e antigen (HbeAg)-negative hepatitis are risk factors for liver fibrosis. In addition, these authors found that interleukin (IL)-1β elevation is important for the progression of liver fibrosis during chronic HBV infection. The mean age of cirrhosis onset in chronic HBV infection acquired during childhood is about 40 years, and the complications become clinically evident 3 years to 5 years later. Cirrhosis development is 3-fold more frequent in chronic HBV patients with a high viral load than in those with a low viral load. HBeAg-positivity and elevated HBV DNA levels were reported as risk factors for the onset of liver cirrhosis in patients with chronic hepatitis B. Liver cirrhosis is a pre-malignant condition that increases the incidence of genetic aberrations and cellular transformations. The chronic hepatic inflammation as well as increased hepatocyte turnover found in cirrhosis lead to genetic mutations. Uncontrolled proliferation and the high rate of genetic mutations promote progression to liver cancer. HBV infection is one of the major risk factors for the development of HCC.

Chronic alcohol intake alters the architecture and compromises the functional capacity of the liver. Alcohol metabolism is catalysed by alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) to acetaldehyde and this major metabolite is the culprit for the majority of the toxic effects associated with alcohol use. Acetaldehyde is both highly toxic and carcinogenic. CYP2E1 is involved in the induction of ROS, which interact with fat molecules thereby causing lipid peroxidation. In addition, both acetaldehyde and CYP2E1 induce oxidative stress. Overall, the effect of alcohol metabolism on protein function, DNA, changes to the immune system and oxidative stress affect both hepatocytes and other liver cells. They take place under both acute and chronic exposure to alcohol and induce significant functional impairments resulting in cell death, tumorigenesis, altered cell-to-cell communication, and make cells more prone to viral infections.

Ethanol metabolism is often associated with viral hepatitis, because the liver is a primary site for both hepatotropic viruses (HCV and HBV) replication and ethanol metabolism. Alcohol-related liver disease accompanied by the hepatitis virus accelerates the disease course. Synergic hepatotoxic effect caused by alcohol and HCV infection increased the risk of advanced liver disease, rapid progression of fibrosis, and higher prevalence of HCC. It has been reported that the combination of HCV infection and daily alcohol intake (> 80 g) increased the risk of HCC development > 100-fold. The incidence of HBV is higher among alcoholics than among the general population. Studies have been conducted on the combined effect of alcohol and viral hepatitis in the progression of liver diseases, but the role of alcohol metabolism as a risk factor in the pathogenesis of HBV infection has not been studied yet.

Alcohol also increases the risk of fibrosis in patients with coexisting HBV, as well as enhances liver necroinflammatory changes in HBsAg-positive patients. There is an increased alteration of liver tests in HBsAg alcohol abusers. In addition, self-resolved HBV infection (defined as HBsAg-negative and HBcAb-positive) can be qualified as a risk factor for developing HCC in patients with alcoholic cirrhosis. Interestingly, a recent study on liver disease progression in subjects with simultaneous presence of HBV/HCV dual infection and a history of alcohol abuse suggests that females are at a higher risk of liver cirrhosis than males. Importantly, the mechanisms of synergistic effects between alcohol and HBV infection, which increases the risk of end-stage liver diseases, should be the subject of extensive research.

HBV replication cycle and alcohol

Under normal circumstances, HBV behaves as a stealth virus, escaping the immune response. HBV is an enveloped DNA virus containing a partially double-stranded relaxed circular DNA genome tropic to hepatocytes. The HBV replication cycle requires binding and entry of the virus via its receptors, cytosolic transport and uncoating of the nucleocapsid, formation of covalently closed circular DNA in the nucleus, the transcription and translation of virus-specific genes, assembly of capsids and initiation of reverse transcription, followed by budding and secretion of virions and sub-viral particles.

Alcoholic patients often have higher levels of HBV markers. Under experimental conditions, it was found that ethanol-fed mice had up to 7-fold higher levels of HBsAg and HBV DNA compared to control diet-fed mice. HBV RNA levels were increased in alcohol-fed mice, also showing higher expression of core, surface, and X antigens in the liver. This is consistent with the higher HBV marker levels present among alcoholics and supports the idea that alcohol abuse increases HBV replication. The ability of HBV to evade and/or suppress the immune system also supports this idea, especially when the immune system is impaired by excessive alcohol consumption. Recently, based on in vitro studies, it was reported that ethanol metabolism increased the HBV RNA, covalently closed circular DNA, and HBsAg in HBV transfected cells. This report is in agreement with a previous study which demonstrated that ethanol significantly increased HBV replication in mice. The mechanism behind the ethanol-induced HBV replication may be related to increased CYP2E1 activity and subsequent oxidative stress induction. As shown by Min et al, ethanol-induced overexpression of CYP2E1 significantly increased the expression of HNF-4a, a major transcription factor for the HBV core promoter, thereby increasing the HBV replication in ethanol-exposed HepAD38 cells. The same authors reported that alcohol per se stimulates the HBV genome transcription by increasing the liver-specific transcription factors/nuclear receptors in an oxidative stress-independent mechanism. In addition, there are other factors, PPARa, FXRa, and PGC involved in the regulation of HBV RNA transcription. They also bind to the HBV core promoter, thereby increasing the transcription of HBV pgRNA. The above-mentioned mechanisms are attributed to ethanol-induced activation of HBV transcription. Recently, it was shown that alcoholic HBV patients have higher hepatitis B viral load. In addition, acetaldehyde affects the lipid composition of cellular membranes in lipid rafts, thereby influencing HBV infectivity. Thus, the increased HBV replication plays a role in the establishment of chronic hepatitis and/or liver end-stage disease in alcohol-abusing HBV patients.

HBV pathogenesis/immunopathogenesis and alcohol

Based on the virus-host interactions, the natural course of chronic HBV infection is subdivided into four stages: (1) Immune-tolerant phase is characterised by HBeAg positivity, and high levels of serum HBV DNA due to active HBV replication. Mostly, children and young adults who are HBsAg-positive for 10-30 years from the initial infection are in this phase; (2) Immune clearance phase accompanied by elevated serum ALT levels and decreased HBV DNA load; and (3) Immune-control phase is characterised by low-replication, patients lose HBeAg with seroconversion to anti-HBeAg, accompanied by liver disease remission; this is typical for the inactive carrier state. However, about 20%–30% of these patients may have a viral relapse followed by reactivation phase during the follow-up period.

There are very limited reports available to support the role of alcohol in HBV pathogenesis in relation to HBV markers. For example, it has been reported that alcohol-abused cirrhotic patients with higher levels of serum HBV DNA are more prone to liver cancer than those with low serum HBV DNA. An increasing HBV DNA levels precipitate the progression of liver cirrhosis to HCC. In another study, the synergism between HBsAg positivity and drinking were reported, suggesting a stronger influence of viral infections and alcohol drinking on the risk of liver cancer. In contrast, as reported by an older study, increased alcohol consumption is related to a higher prevalence of HBeAg seroconversion to anti-HBe, increased prevalence of ALD and lower prevalence of chronic hepatitis. Furthermore, some early studies demonstrated more frequent presence of anti-HBs and anti-HBc antibodies in the blood of alcoholics than in non-alcoholics. In addition, it has been shown that alcohol consumption increased liver necro-inflammatory changes in HBsAg-positive patients and elevated liver tests.

Role of alcohol in HBV innate immunity

Host cells activate the innate immune response when they contact a pathogen to prevent the spread of infection and to stimulate efficient adaptive immune response. Pattern-recognition receptors, through identifying the specific pathogen determinants, activate innate immunity to protect against pathogens. Viral sensing, induction of type I IFNs and production of different cytokines are performed via toll-like receptors (TLRs), RNA helicases, RIG-I-like receptors, NOD-like receptors, melanoma differentiation-associated protein 5 and protein kinase R. Namely, TLR5, and TLR9 are receptors for viral DNA, TLR7 and TLR8 for single-stranded RNA, while TLR3 can bind double-stranded RNA.

Production of IFN type 1 -α/β and activation of natural killers (NK) cells are induced at the initial phase of viral infections. Infected plasmacytoid dendritic cells (pDC) are the main producers of IFN-α/β, while NK and natural killer T (NKT) cells produce IFN-γ. In addition to IFN-α/β, other cytokines, like IL-12 and IL-18, control viral replication.

HBV is relatively inefficient at inducing the anti-viral cytokines, including IFN-α/β. This appears to be due to limited sensing of the HBV stealth virus combined with active suppression of innate immunity. IFN-α/β-induced interferon inducible genes (ISGs) are responsible for antiviral effects that minimise pathogenetic processes by limiting the viral production and spread. Studies conducted on acutely infected chimpanzees as well as in humans showed decreased production of type-1 interferons and ISGs. Interestingly, using a transgenic mouse model or hepatoma cell lines, it has been shown that HBV replicates at higher levels in IFN-γ knockouts and IFN-α/β receptor knockouts mice than in wild-type mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. In support of the above study, it was demonstrated that HBV elicits a strong and specific innate antiviral response (production of IFN-β and activation of ISGs) that results in a non-cytopathic clearance of HBV DNA in HepaRG cells. In contrast, in a chimeric mouse model, HBV inhibited the nuclear translocation of STAT1 in response to IFNα, thereby preventing ISG transcription in human hepatocytes. The effect of ethanol on IFN-α/β innate responses and ISGs activation in HBV infection pathogenesis has not been investigated, but there are several studies which suggest that alcohol impairs IFN-α/β innate responses and anti-viral gene expressions in HCV pathogenesis. Future studies should focus on understanding the effect of alcohol metabolism on IFN-α/β innate responses and ISGs activation during HBV infection pathogenesis as well as examine whether IFN-α/β therapy could be a useful strategy for HBV alcoholics.

HBV infection may elicit differential cytokine responses among various liver cell types, which differ from hepatocytes, depending on the stage or route of infection. Both in vitro and in vivo studies showed that TNF-α, IL-12, and IL-18 are involved in controlling HBV replication in addition to IFN-γ and IFN-α/β induction. Several cytokines control HBV transcription through liver-enriched transcription factors. It has been demonstrated that IL-4, IL-6, IL-1β, and transforming growth factor-β (TGF-β) were effective in diminishing HBV replication markers via regulating HBV transcriptional activity. However, while all these cytokines are protective during acute HBV infection, their persistence in chronic infection may cause liver inflammation.

While the effect of alcohol in modulating these cytokines in HBV infection has not been investigated, it has been well documented that pro-inflammatory cytokines levels were increased and anti-inflammatory cytokines were decreased in ALD patients. Taken together, it is reasonable to expect that alcohol could affect the anti-viral activity of these cytokines during acute infection and potentiate persistent liver inflammation in chronic HBV infection, thereby promoting progressive end-stage liver diseases. The excessive or persistent presence of immune mediators in tissues have been recognised to play important roles in the pathogenesis of human diseases. It is very important to conduct future studies to understand and fill the gaps in our understanding of the role of alcohol in both acute and chronic HBV infection-induced cytokine responses.

Being an important innate immunity component, NK cells control viruses via direct or indirect cytolytic effects, namely, through the release of cytokines, IFN-γ, TNF-α, TGF-β and IL-10. In this regard, NK cell can directly lyse infected hepatocytes through granzyme/perforin or death receptor pathways causing the death of infected hepatocytes. Non-cytolytic mechanisms of HBV clearance through cytokines like IFN-γ also control the virus in the infected liver without affecting cell integrity.

The antiviral capacity of NK cells in HBV-infection has been extensively reviewed by two different groups. In this regard, NK cells efficiently inhibited HBV replication in a transgenic mice mouse model of HBV infection and contributed to HBV clearance using an acute HBV mouse model. In chimpanzees, NK cells participated early in non-cytolytic clearance of HBV-infected hepatocytes accompanied by an increase in intrahepatic content of IFN-gamma and TNF-α. However, subsequent experiments revealed a critical role for T cells rather than NK cells in HBV control in this model. In the pre-clinical ramp-up phase of acute hepatitis B patients, it was observed an increase in the number of circulating NK cells, while activation and effector function was suppressed; this led to viral load increase. There was an inverse correlation between low NK cell activation and induction of the immunosuppressive cytokine IL-10, raising the possibility that HBV can actively evade immune responses.

NK cells display varying changes in proportion, phenotype and/or function in different studies of chronic HBV infection. The defects in NK cells are reflected in many aspects: In chronic HBV patients: (1) The proportions of hepatic and peripheral NK cells are reduced with or without changes in their subsets; (2) There are changes in the expression of activating or inhibitory receptors on NK cells; (3) There is an increase of some molecules with negative effects, such as T cell immunoglobulin and mucin domain containing molecule-3; (4) The cytolytic activity is maintained or even enhanced, which correlates with the severity of liver injury; and (5) There is a defect in the production of cytokines, like IFN-γ and TNF-α, making them inefficient in the promotion of direct non-cytolytic antiviral roles as well as in T-cell responses.

Activated NK cells play a role in early HBV-infected hepatocyte clearance. However, with the progression of chronic infection, both NK and T cells can be suppressed by tolerogenic effects of hepatic ligands and cytokines which limit their antiviral efficacy. Further studies are needed for better understanding of the factors triggering and mediating the opposing roles of NK cells in chronic HBV infection which could allow these cells to be successfully exploited as therapeutic targets. Importantly, the role of alcohol on NK cell responsiveness in the HBV-infected liver has not been addressed. As reported, NK cells are impaired by alcohol, which ultimately affects antiviral activity of NK cells during acute HBV infection. Another possible mechanism is the alcohol-induced impairment of IFN-γ signalling which would decrease the protective ISGs gene expression. It was recently reported that ethanol metabolite, acetaldehyde impaired IFN-γ signalling via the JAK-STAT1 pathway in HBV transfected cells. Future studies in this topical area will improve our understanding of NK cell immunity in HBV-infected alcoholic patients.

Dendritic cells (DCs), (both conventional/myeloid DCs, mDCs and plasmacytoid DCs, pDCs) effectively connect the adaptive and innate immune responses. Subpopulations of DCs can

Excessive alcohol use is related to an increased risk of spreading hepatitis B virus infection

Excessive alcohol consumption can lead to hepatitis, an inflammation of the liver. Alcohol is a toxin that is metabolised by the liver, and heavy alcohol use can overload the liver with toxins, causing inflammation and injury. Hepatitis B is a virus that can also cause inflammation of the liver. The combination of hepatitis B and heavy alcohol use can therefore lead to more severe liver damage.

Alcohol can increase the replication of hepatitis B and possibly other hepatitis viruses, as well as increase oxidative stress and cytotoxicity, and decrease antiviral immune responses in the liver. This can lead to an increased risk of developing liver cirrhosis and hepatocellular carcinoma (HCC).

The risk of developing HCC is higher in those with chronic hepatitis B and heavy alcohol use than in those with hepatitis B alone. The risk of developing HCC is also higher in those with hepatitis B and heavy alcohol use than in those with hepatitis B and light-to-moderate alcohol use. However, the influence of light-to-moderate alcohol drinking on the hepatitis B-induced liver fibrosis, cirrhosis, and HCC among patients infected with hepatitis B remains unclear.

The mechanisms underlying the complex interaction between alcohol and hepatitis viruses are not fully understood, and more research is needed.

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