Coffee consumption and the development of hepatocellular carcinoma in HBV

Coffee consumption and the development of hepatocellular carcinoma in HBV

The latest issue of Liver International investigates the effect of coffee consumption on the development of hepatocellular carcinoma in hepatitis B virus endemic area.

Coffee consumption is inversely related to the risk of cirrhosis or hepatocellular carcinoma. However, the protective effect of coffee drinking against the risk of hepatocellular carcinoma was not established in HBV-prevalent region. Dr Eun Sun Jang and colleagues from Korea elucidated the relationship between lifetime coffee consumption and the risk of hepatocellular carcinoma development under the consideration of replication status of HBV.

A hospital-based case–control study was performed in 1364 subjects. A total of 258 hepatocellular carcinoma patients, 480 health-check examinees and 626 patients with chronic liver disease other than hepatocellular carcinoma were interviewed on smoking, alcohol and coffee drinking using a standardized questionnaires.

High lifetime coffee consumption was negatively associated with hepatocellular carcinoma

Liver International

After adjustment for age, gender, obesity, DM, presence of hepatitis virus and lifetime alcohol drinking/smoking, a high lifetime coffee consumption was an independent protective factor against hepatocellular carcinoma, in each analyses using healthy and risky control groups respectively. However, the high coffee consumption did not affect the hepatocellular carcinoma risk in patients with HBV after adjustment for HBeAg status, serum HBV DNA level and antiviral therapy.

Dr Jang's team concludes, "A high lifetime coffee consumption was negatively associated with a hepatocellular carcinoma development." "However, this difference of coffee exposure with the hepatocellular carcinoma group was reduced in chronic hepatitis B patients by the dominant role of viral replication."

Liver International 2013: 7(33): 1092–1099
25 July 2013 

Bermuda Triangle for the liver: Alcohol, obesity, and viral hepatitis

Bermuda Triangle for the liver: Alcohol, obesity, and viral hepatitis

1. Samir Zakhari

Article first published online: 15 JUL 2013

DOI: 10.1111/jgh.12207

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

 

Journal of Gastroenterology and Hepatology

Special Issue: 7th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis. Funding for this conference was made possible (in part) by Grant 5 R13AA20691-02 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Guest Editors: Bin Gao and Fu-Sheng Wang

 

Volume 28, Issue Supplement S1, pages 18–25, August 2013

 

Abstract

Despite major progress in understanding and managing liver disease in the past 30 years, it is now among the top 10 most common causes of death globally. Several risk factors, such as genetics, diabetes, obesity, excessive alcohol consumption, viral infection, gender, immune dysfunction, and medications, acting individually or in concert, are known to precipitate liver damage. Viral hepatitis, excessive alcohol consumption, and obesity are the major factors causing liver injury. Estimated numbers of hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected subjects worldwide are staggering (370 and 175 million, respectively), and of the 40 million known human immunodeficiency virus positive subjects, 4 and 5 million are coinfected with HBV and HCV, respectively. Alcohol and HCV are the leading causes of end-stage liver disease worldwide and the most common indication for liver transplantation in the United States and Europe. In addition, the global obesity epidemic that affects up to 40 million Americans, and 396 million worldwide, is accompanied by an alarming incidence of end-stage liver disease, a condition exacerbated by alcohol. This article focuses on the interactions between alcohol, viral hepatitis, and obesity (euphemistically described here as the Bermuda Triangle of liver disease), and discusses common mechanisms and synergy.

The global burden
 

Liver cirrhosis and hepatocellular carcinoma (HCC) represent end-stage liver disease (ESLD) and thus are associated with mortality. Globally, the incidence and prevalence of liver cirrhosis vary markedly based largely on the causative factors. In the developed world, alcohol, hepatitis C virus (HCV), and nonalcoholic steatohepatitis are the leading causes of cirrhosis, whereas viral hepatitis (especially hepatitis B virus [HBV]) is considered the leading cause in developing countries. Data from 2001 indicate that in developed countries, cirrhosis was the sixth most common cause of death among adults, and in developing countries, it claimed 320 000 lives, ranking as the ninth most common cause of death. In the European Union alone, approximately 29 million individuals suffer from chronic liver disease of whom 170 000 and 47 000 die annually from cirrhosis and liver cancer, respectively.[1] In the United States, approximately 46 700 individuals died from liver cirrhosis and cancer in 2002.[2] HBV and HCV infection are major causes of morbidity and mortality. According to World Health Organization, an estimated 2 billion people have been infected with HBV, and more than 240 million have chronic liver infections worldwide. About 600 000 people die every year from the acute or chronic consequences of HBV infection, which is endemic in China and other parts of Asia, where most people become infected during childhood; 8–10% of the adult population is chronically infected. HBV-induced liver cancer is among the top three causes of death from cancer in men, and a major cause of cancer in women in this region. Globally, cirrhosis attributable to HBV or HCV accounted for 30% and 27%, respectively, and HCC was attributable to HBV (53%) or HCV (25%). Applied to 2002 worldwide mortality estimates, chronic HBV and HCV infections represent 929 000, including 446 000 cirrhosis deaths (HBV: 235 000; HCV: 211 000) and 483 000 liver cancer deaths (HBV: 328 000; HCV: 155 000).[3]
 

Nonalcoholic fatty liver disease (NAFLD) comprises a wide spectrum of liver damage including steatosis, steatohepatitis, fibrosis, and cirrhosis in patients who do not consume large amount of alcohol.[4] NAFLD is a significant factor for serious liver disease because of its rising prevalence in the general population,[5] and the potential to progress to ESLD and HCC.[6] NAFLD commonly occurs in patients with obesity, diabetes, and hyperlipidemia. In the past two decades, obesity in North America has more than doubled and continues to rise worldwide. In 2005, 8% of men and 12% of women were obese. By 2030, the number of obese adults globally is projected to be 573 million individuals.[7]
 

The combination of chronic heavy alcohol consumption, viral hepatitis infection, and obesity represent a major assault on liver's health worldwide.

Alcoholic liver disease (ALD)

Chronic alcohol consumption results in liver disease which varies extensively between individuals in severity and progression for comparable levels of alcohol consumption. This variability could be attributed to variations in the expression and activity of individual isoforms of the alcohol-metabolizing enzymes: alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), but is also influenced by variations in patterns of alcohol intake (binge vs chronic drinking), nutritional status, gender, smoking, or abuse of other drugs. In addition, the onset and severity of ALD is strongly influenced by other comorbid conditions such as obesity or HCV infection. This increase in susceptibility to ALD is not due solely to intrahepatic factors, but may also involve alcohol-induced changes in other tissues, such as adipose tissue, central nervous system, the gut, and the immune system. Factors contributing to alcohol-induced liver disease are thus complex and systemic.[8] The spectrum of ALD includes:

1. Fatty liver (hepatic steatosis), characterized histologically by lipid droplets in hepatocytes. This condition is usually reversible upon cessation of alcohol consumption, and thus is thought to be a relatively innocuous side effect of heavy drinking. However, hepatic steatosis often develops in obesity, metabolic syndrome, and type 2 diabetes, clinical conditions that involve significant metabolic defects. Thus, fatty liver by itself reflects a condition of metabolic stress that is a risk factor for the development of more severe forms of liver disease.
2. Alcoholic hepatitis, an inflammatory condition characterized by significantly increased serum levels of liver enzymes (alanine aminotranferease and aspartate aminotransferase) and moderate to severe tissue damage, including necrotic foci with neutrophil infiltration. Acute alcoholic hepatitis is a potentially fatal disease that develops in a significant fraction (30–40%) of chronic heavy drinkers.
3. Liver fibrosis/cirrhosis, about 10–15% of chronic heavy drinkers proceed to develop fibrosis and cirrhosis.
4. HCCs occur in about 2% of cirrhotic patients.

Although factors that facilitate the development of hepatitis and cirrhosis are not well characterized, impairment in the cellular stress defense mechanisms, (e.g. oxidative stress),[9] or derailment of the balance of autocrine or paracrine mediators that are critical in maintaining normal homeostatic conditions are documented. In addition, chronic alcohol consumption interferes with liver regeneration, which under normal conditions is a highly effective repair mechanism that avoids scar tissue formation.

Mechanisms of ALD
 

Various mechanisms have been identified for ALD (Fig. 1) which are involved at various stages of progression.

 

Figure 1. Known mechanisms of alcoholic liver damage. CB, cannabinoid receptor; ER, endoplasmic reticulum; Fe, Ferrous molecule; HCC, hepatocellular carcinoma; HNE, 4-hydroxynonenal; HSC, hepatic stellate cell; KC, Kupffer cells; LPS, lipopolysaccharide; MAA, malondialdehyde-acetaldehyde adduct; MDA, malondialdehyde; Mt GSH, mitochondrial glutathione; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; ROS, reactive oxygen species; TGF, transforming growth factor

 

Fatty liver

 

Both intrahepatic and extrahepatic mechanisms are involved in hepatic steatosis:

• a) Intrahepatic factors

Hepatic steatosis due to heavy alcohol consumption has been attributed to a metabolic stress imposed by the fact that the liver is the predominant site of ethanol metabolism. Possible mechanisms include: (i) suppression of mitochondrial fatty acid β-oxidation; (ii) a limitation in the permeability of the outer mitochondrial membrane pore protein voltage-dependent anion-selective channel;[10] (iii) enhancement of hepatic uptake of free fatty acids from the circulation; (iv) increase in de novo synthesis of fatty acids and triglycerides; and (v) derailment of lipoprotein synthesis and secretion.

Chronic alcohol consumption induces a marked increase in cytochrome P450 2E1 (CYP2E1) activity, with a resultant increased demand for nicotinamide adenine dinucleotide phosphate (NADPH), an increased rate of formation of reactive oxygen species (ROS), and a decrease in oxidative stress defense capacity. At the same time, impairment of mitochondrial respiratory capacity caused by defects in the electron transport and ATP synthase complexes results in further increase in ROS formation at the mitochondrial level.[11] The ethanol-induced stress is further exacerbated by defects in the methionine cycle, resulting in a decrease in glutathione (GSH) synthesis, which contributes to the decline in oxidative stress defenses. Importantly, these conditions also reflect an increase in endoplasmic reticulum (ER) stress, a common response do the accumulation of defective proteins.[12] The resulting accumulation of stress conditions in hepatocytes causes an increased susceptibility to cell death signals. Accompanying the structural and functional changes in subcellular organelles, chronic ethanol treatment results in significant changes in the profile of transcription factors that regulate lipid homeostasis in the liver. Ethanol consumption elicits a decrease in peroxisome proliferator-activated receptor (PPAR)-α activity, thereby suppressing the catabolic lipid metabolic pathways, including peroxisomal and mitochondrial fatty acid oxidation. At the same time, ethanol increases the activity of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which enhances lipid synthetic pathways. In addition, there has been some evidence that the adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited by ethanol. However, it is difficult to distinguish direct and indirect effects of ethanol. For instance, AMPK activity in the liver is regulated not only by the availability of AMP in the cell, but also responds to extracellular signals, including the adipose tissue derived cytokine adiponectin.
 

A related regulatory pathway affected by ethanol may involve the deacetylase silent information regulator-1 (SIRT-1), which requires activation by nicotinamide adenine dinucleotide (NAD⁺). Thus, the change in NAD redox state in the liver during ethanol oxidation may facilitate inhibition of SIRT-1. It has been reported that SIRT-1 activity in the liver of mice is decreased after ethanol treatment.[13] Among the targets of SIRT-1 are several key regulators of lipid metabolism, including the transcriptional coregulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Its deacetylation by SIRT-1 allows it to stimulate gene expression through its interactions with PPAR-α. Furthermore, SREBP-1c is a target for SIRT-1 and its acetylation state may affect its transcriptional activity.

• b) Extrahepatic factors

Lipid metabolism in the liver is integrated with a variety of signals, including circulating hormones, cytokines, nutrition, and other factors that impinge on the intrahepatic processes leading to steatosis. While some of these factors are intrahepatic (e.g. cytokines released from Kupffer cells, endothelial cells, or stellate cells), others are dispatched by remote tissues. Of particular relevance are hormones (e.g. insulin), adiponectin and leptin (secreted from adipose tissue), and stress hormones and satiety factors that act through the hypothalamus or other brain structures to regulate food intake. Chronic ethanol consumption has a notable impact on the synthesis and secretion of several of these factors, in addition to affecting their capacity to impact lipid metabolic pathways in the liver.
 

Adiponectin, one of the adipokines secreted by adipose tissue to regulate lipid homeostasis, acts on multiple tissues including the liver to sensitize the response to insulin and enhance fatty acid oxidation. In animal experiments, ethanol feeding tends to suppress adiponectin secretion from adipose tissue. However, the effects of ethanol on adiponectin levels may depend on dietary factors such as the content of saturated and unsaturated fat.[14] Whether circulating adiponectin levels are similarly correlated with liver damage in human alcoholics remains unclear.[15]
 

Insulin plays a dominant role in integrating fatty acid and carbohydrate metabolism in the liver with the energetic needs of other tissues. Nonalcoholic hepatic steatosis that occurs in the metabolic syndrome and type II diabetes is commonly associated with insulin resistance, that is, a decreased capacity to respond to changes in circulating insulin, in multiple tissues including liver and muscle. There is strong evidence that stress responses mediated by free fatty acid accumulation or ER stress result in activation of stress response protein kinases, including protein kinase C and Jun-N-terminal kinase, which affect the intracellular signaling pathways through which insulin exerts its effects.

Alcoholic hepatitis
 

As described earlier, hepatic steatosis represents a severe condition of increased oxidative stress, ER, and metabolic stress. However, the mechanisms by which such stress conditions can lead to a more severe inflammatory condition remain only partly understood. Increased cell death (by necrosis or apoptosis) sets in motion further pro-inflammatory responses in the liver by producing cytokines and chemokines that help mobilize neutrophils and other inflammatory cells that further enhance liver damage. Also, it appears that overproduction of ROS by the damaged mitochondria could play a salient role. Factors that may be involved in the precipitation of alcoholic hepatitis are briefly discussed later.

Oxidative alcohol metabolism in the liver
 

Only about 2–10% of the absorbed alcohol is eliminated via the lungs and kidneys; the remaining 90% is metabolized mainly by oxidative pathways in the liver and by nonoxidative pathways in extrahepatic tissues. Oxidative metabolism in the liver results in extensive displacement of the liver's normal metabolic substrates, the production of acetaldehyde and ROS, and an increase in the NADH/NAD⁺ ratio (Fig. 2).

 

Figure 2. Hepatitis C virus (HCV), alcohol metabolism, and liver damage. ALD, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; GSH, glutathione; HCC, hepatocellular carcinoma; IFN, interferon; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NADP, nicotinamide adenine dinucleotide phosphate; RNS, reactive nitrogen species; ROS, reactive oxygen species.

The major pathway of oxidative metabolism of ethanol in the liver involves multiple isoforms of cytosolic ADH, which results in the production of acetaldehyde. Accumulation of this highly reactive and toxic molecule contributes to liver damage. The oxidation of ethanol is accompanied by the reduction of NAD⁺ to NADH and, thereby, generates a highly reduced cytosolic environment in hepatocytes. The cytochrome P450 isozymes, including CYP2E1, 1A2, and 3A4, which are predominantly localized to the ER, also contribute to ethanol's oxidation to acetaldehyde in the liver. CYP2E1 is induced by chronic ethanol consumption and assumes an important role in metabolizing ethanol to acetaldehyde at elevated alcohol concentration. It also produces ROS, including hydroxyethyl, superoxide anion, and hydroxyl radicals.

Acetaldehyde, produced by ethanol oxidation, is rapidly metabolized mainly by mitochondrial ALDH2 to form acetate and NADH. Mitochondrial NADH is reoxidized by the electron transport chain (ETC). Most of the acetate resulting from ethanol metabolism escapes the liver to the blood and is eventually metabolized to CO₂ by way of the tricarboxylic acid cycle in tissues such as heart, skeletal muscle, and brain, where mitochondria are capable of converting acetate to the intermediate acetyl coenzyme A.

Consequences of alcohol metabolism by oxidative pathways
 

• a) Acetaldehyde generation/adduct formation: if accumulated to high concentrations, acetaldehyde can form adducts with DNA and RNA, and decrease DNA repair. It also has the capacity to react with lysine residues on proteins including enzymes, microsomal proteins, microtubules, and affect their function. Formation of protein adducts in hepatocytes may contribute to impaired protein secretion, resulting in hepatomegaly. In addition, acetaldehyde and malondialdehyde (a by-product of lipid peroxidation) can combine and react with lysine residues on proteins, giving rise to stable malondialdehyde-acetaldehyde-protein adducts that are immunogenic and, thus, can contribute to immune-mediated liver damage.
• b) Change in hepatocyte redox state (increase in NADH/NAD⁺ ratio): both acute and chronic alcohol consumption shift the redox state of the liver to a more reduced level, similar to but more pronounced than the shift observed in diabetes and during starvation. Alcohol metabolism produces a significant increase in the hepatic NADH/NAD⁺ ratio in both the cytosol and the mitochondria, as evidenced by an increase in the lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios, respectively, and vastly increases the availability of oxidizable NADH to the ETC in the mitochondria. The liver responds to ethanol exposure in part by increasing the rate of oxygen uptake, which may lead to periods of hypoxia, particularly in the downstream (pericentral) parts of the liver lobule.
• c)Formation of ROS, reactive nitrogen species (RNS), and oxidative stress: Hepatic mitochondria produce ROS through the activity of the ETC as a by-product of oxidative phosphorylation. Normally, a small fraction of electrons entering the ETC can prematurely escape from complexes I and III and directly react with 1–3% of respiratory oxygen molecules to generate the superoxide anion radical, which is then dismutated by the mitochondrial manganese superoxide dismutase into hydrogen peroxide (H₂O₂). Mitochondrial glutathione peroxidase (GPx) then converts H₂O₂ into water by using reduced glutathione (GSH) as a cofactor. Thus, most of the ROS generated by the ETC in the normal state are detoxified by the mitochondrial antioxidant defenses. The nondetoxified portion of ROS diffuses out of mitochondria, and affects signal transduction pathways and gene expression, triggering cytokines, hormones, and growth factors, which if excessive may lead to hepatic inflammation, necrosis, and/or apoptosis. In addition, metals (e.g. iron and copper) can further react with H₂O₂ to produce hydroxyl radicals via the Fenton reaction (Fig. ).

Figure 3. Alcohol, reactive oxygen species (ROS), and mitochondrial dysfunction. CYP2E1, cytochrome P450 2E1; GSH, glutathione; GSSG, oxidized glutathione; H2O2, hydrogen peroxide; MnSOD, manganese superoxide dismutase; NO●, nitric oxide; O₂●^–, speroxide; ●OH, hydroxyl radical; ONOO^–, peroxinitrite.

Nitric oxide (NO), an RNS critical for hepatocyte biology, can interact with peroxides to generate peroxynitrite, which could be detrimental to the liver depending on the amount and duration. NO is produced by inducible nitric oxide synthase which is expressed in all liver cells (i.e. hepatocytes, stellate cells, Kupffer cells, and vascular endothelial cells) and its expression is induced by interleukin (IL)-1β alone or in combination with tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and/or lipopolysaccharide (LPS).
 

Ethanol-induced oxidative stress has been attributed to a decrease in the NAD⁺ : NADH ratio, acetaldehyde formation, CYP2E1 induction, hypoxia, cytokine signaling, mitochondrial damage, LPS activation of Kupffer cells, reduction in antioxidants particularly mitochondrial and cytosolic GSH, one electron oxidation of ethanol to 1-hydroxy ethyl radical, and the conversion of xanthine dehydrogenase to xanthine oxidase.

Fibrosis and cirrhosis

Fibrosis is a common response of the liver to a chronic inflammatory condition, where hepatic stellate cells (HSC) play a critical (though not exclusive) role.[19] HSCs exist in a quiescent state in the normal liver, but can be activated directly or indirectly in response to apoptotic or necrotic cell death. Cytokines released in the tissue as a result of injury further contribute to HSC activation, resulting in the expression of a myofibroblast phenotype and stimulating the expression of extracellular matrix (ECM) proteins, in particular collagen type 1, which are not normally expressed in the liver. Under conditions of an acute tissue injury, the deposition of collagen fibers is a transient wound-healing response and is followed by fibrinolysis mediated by metalloproteases that are activated as damaged tissue is replaced by newly generated liver cells by the regenerative response. Continuous tissue damage and repair after chronic inflammation, and an imbalance in the normal liver repair mechanisms results in excessive deposition of collagen fibers.[19]
 

Chronic ethanol consumption can influence this process at multiple levels: (i) enhancement of the pro-inflammatory environment in the liver by stimulating the release of pro-inflammatory cytokines from macrophages and decreasing the activity of protective cell types, including natural killer cells;[20] (ii) enhancement of hepatocyte apoptosis and necrosis in response to oxidative stress and shifting in stress defense signaling pathways; (iii) activation of HSCs and collagen formation (studies on isolated HSCs have demonstrated that ethanol alters their response to transforming growth factor (TGF-β) and IFN-γ through effects on intracellular signaling pathways); and (iv) suppression of the regenerative response to tissue damage that is an essential component of the liver's repair mechanism and thereby facilitates the deposition of scar tissue, which is the hallmark of fibrosis. This is probably accompanied by a suppression of metalloproteases (e.g. by the activation of inhibitor proteins, such as plasminogen activator inhibitor-1 [PAI-1]), which normally would maintain the balance of ECM deposition and resolution to facilitate tissue repair.[21]

Common factors involved in alcohol, obesity, and viral infection

Chronic heavy alcohol consumption, obesity, and viral infection have some common features/mechanisms that may contribute to exacerbation of liver damage when these conditions coexist. Several common mechanisms between two or more of these conditions have been advocated, including oxidative stress, CYP2E1 induction, increased fat synthesis and mobilization, selected gut bacteria, free fatty acids, ER stress, immune response, among others.[22-25] Because of page limitations, only the first two mechanisms (oxidative stress and CYP2E1 induction) will be discussed. Oxidative stress due to alcohol has been discussed earlier.

Obesity and oxidative stress

Obesity involves the accumulation of body fat and is a major risk factor for metabolic syndrome, which is characterized by hyperglycemia, dyslipidemia, and hypertension.[26] Increased oxidative stress in accumulated fat has been reported as a pathogenic mechanism of obesity-associated metabolic syndrome. In nondiabetic humans, systemic oxidative stress correlated positively with fat accumulation and negatively with plasma adiponectin levels. In obese mice, ROS production was selectively increased in adipose tissue, and was accompanied by enhanced expression of NADPH oxidase and decreased expression of anti-oxidative enzymes such as superoxide dismutase in white adipose tissue and GPx in liver.[27] In cultured adipocytes, mitochondrial and peroxisomal oxidation of fatty acids activates NADPH oxidase resulting in increased oxidative stress, which caused increase in messenger RNA (mRNA) expression of inflammatory (PAI-1, TNF-α, IL-6, and monocyte chemotactic protein-1), and suppression of mRNA and secretion of anti-inflammatory (adiponectin, leptin) adipocytokines. Conversely, in obese KKAy mice, treatment with apocynin, an NADPH oxidase inhibitor, reduced ROS production in adipose tissue, increased plasma adiponectin levels, and improved hyperlipidemia and hepatic steatosis. Because oxidative stress underlies the pathophysiology of hepatic steatosis,[28] these results suggest that increased oxidative stress in obese individuals could be further exacerbated by oxidative stress due to chronic heavy alcohol consumption.

Viral infection and oxidative stress

Infection with HCV, in most cases, develops into chronic disease which is manifested by steatosis and fibrosis, as well as HCC. HCV replication induces oxidative stress (Figure 2), which contributes to insulin and interferon resistance, as well as disorders of iron metabolism. Specifically, virus core and nonstructural NS5A proteins increase ROS levels through alteration of calcium homeostasis[29] via a primary effect on the uniporter,[30] and the induction of NADPH oxidase 4.[31] In addition, E1 and E2 and the transmembrane protein NS4B increase ROS generation via ER stress and unfolded protein response,[32, 33] and activates the antioxidant defense regulated by NF-E2-related factor 2.[34] Furthermore, HCV causes mitochondrial damage and induction of double-stranded DNA breaks mediated by NO and ROS, which is abolished by NO and ROS inhibitors.[35] HCV-induced ROS causes hepatic iron accumulation in mice by reducing hepcidin transcription, further magnifying ROS production,[36] and regulating TGF-β1.[37]

CYP2E1, alcohol, and oxidative stress

As mentioned earlier, alcohol-induced oxidative stress is a major mechanism by which ethanol causes liver injury. Of the many suggested pathways by which ethanol induces a state of oxidative stress, induction of CYP2E1 is a central one. Levels of CYP2E1 are increased after acute and chronic alcohol treatment. CYP2E1 generates ROS such as the superoxide anion radical and hydrogen peroxide and, in the presence of iron catalysts, produces the hydroxyl radical, a powerful oxidant (Figure 3). The role of CYP2E1 in chronic ethanol-induced liver injury was studied in wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Alcohol produced oxidant stress and steatosis in WT mice, but these effects were blunted in the KO mice and restored in the KI mice. These studies show that CYP2E1 contributes to ethanol-induced oxidant stress and liver injury.[38] For a discussion of the biochemical and toxicological properties of CYP2E1 and possible therapeutic implications for treatment of ALD by CYP2E1 inhibitors, the reader is referred to the review article by Lu and Cederbaum.[39]

CYP2E1, obesity, and oxidative stress

As discussed earlier, CYP2E1 is an important factor in liver disease. Several studies suggest that hepatic CYP2E1 activity is increased in patients with nonalcoholic steatohepatitis, chronic alcoholism, or morbid obesity. To study the correlation between obesity and CYP2E1, Emery et al.[40] assessed hepatic CYP2E1 activity—by determining the clearance of chlorzoxazone (CLZ), a CYP2E1-selective probe—in morbidly obese subjects with varying degrees of hepatic steatosis, and normal-weight controls. Obese subjects were evaluated at baseline and 1 year after gastroplasty, a procedure that leads to weight loss. Compared with controls, oral CLZ clearance was elevated approximately threefold in morbidly obese subjects, and was significantly higher among subjects with steatosis involving > 50% of hepatocytes. One year after gastroplasty, the median body mass index decreased by 33%, and total oral CLZ clearance declined by 46%. Thus, hepatic CYP2E1 activity is upregulated in morbidly obese subjects, and the positive association between the degree of steatosis and CYP2E1 activity preoperatively suggests that CYP2E1 induction is related to morbid obesity.[40] Similar results were obtained in genetically obese Zucker rats fed a normal diet (OB) when compared with normal Zucker rats fed a high-fat diet (HF). CYP2E1 induction was greater in both liver and fat of OB rats than in those of HF rats. The induction of CYP2E1 in liver and fat of obese patients may potentially alter the pharmacokinetics of lipophilic drugs metabolized by CYP2E1.[41]
 

In a recent study, Cederbaum reported that CYP2E1 induction potentiated liver injury in obese mice, and the elevated oxidative stress could be blunted by CYP2E1 inhibitors.[38] In addition, S-Adenosyl-L-methionine decreased oxidative stress, steatosis, liver injury, and mitochondrial dysfunction in the pyrazole-treated obese mice, an important finding with therapeutic implications in obesity-induced metabolic complications.

 

CYP2E1, HCV, and oxidative stress

CYP2E1 expression in the liver of patients with chronic hepatitis C correlated with the progression of hepatic disease (both lobular inflammation and fibrosis indices), and observed variations were consistent with the preferential distribution of CYP2E1 in the lobular zone.[42] The effect of alcohol metabolism on HCV replication and the antiviral action of IFN was studied in Huh-7 cells that harbor HCV replication and metabolize ethanol via the introduced expression of CYP2E1. Alcohol (up to 100 mmol/L) significantly increased HCV replication, which was dependent on CYP2E1 expression and alcohol-induced oxidative stress, and attenuated the anti-HCV action of IFN.[43] In chronic hepatitis C patients, cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.[44]

Alcohol's elevation of HCV titer in patients and increase of HCV RNA in replicon cells suggest that HCV replication is increased in the presence and absence of the complete viral replication cycle. Seronello et al.[45] used Huh7 human hepatoma cells that naturally express comparable levels of CYP2E1 as human liver to demonstrate that ethanol, at physiologically relevant concentrations, enhances complete HCV replication. Acetaldehyde, the first metabolite of ethanol, also enhanced HCV replication. They reported that elevated NADH/NAD+ is required for the potentiation of HCV replication by ethanol, and inhibiting CYP2E1 or ALDH suppressed replication. Thus, alteration of cellular NADH/NAD ratio is likely to play a critical role in the potentiation of HCV replication by ethanol (Fig. 4).

 

 

Figure 4. Summary of alcohol and HCV interactions. HCV, hepatitis C virus; IFN, interferon; ROS, reactive oxygen species.

 

Concluding remarks

 

Chronic heavy alcohol consumption in the presence of obesity and viral hepatitis could be damaging for the liver. While moderate alcohol consumption was associated with decreased prevalence of steatohepatitis in patients with NAFLD,[46] heavy alcohol consumption is discouraged whether an individual has NAFLD or not. The presence of common mechanisms for liver damage due to viruses, obesity, or chronic heavy alcohol consumption is relevant and may exacerbate damage to the liver when these three conditions exist. Further research is needed to clarify the interaction, if any, between moderate drinking, NAFLD, and viral hepatitis.

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Updates: Women With Chronic Hepatitis C Virus Infection

 

July Updates @  Hepatitis C New Drug Research And Liver Health

 

Filter through the many July updates on the website by clicking on the links provided below. Topics include; liver health, updated research on current or new therapies in development to treat hepatitis C, videos and more.

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All Updates: Women and HCV

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Women With Chronic Hepatitis C Virus Infection Recommendations for Clinical Practice

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus  occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited...

 

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All Updates: Treating Children With HCV

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NICE draft guidance recommends drugs to treat chronic hepatitis C in children and young people

In draft guidance published today NICE recommends peginterferon alfa in combination with ribavirin as an option for treating chronic hepatitis C in children and young people.

 

Association of IL28B polymorphisms with virological response to peginterferon and ribavirin therapy in children and adolescents with chronic hepatitis C.

Among pediatric patients with HCV infection the effectiveness of PEG-IFN/RBV therapy may be lower in the group with genotype-1 IL28B minor alleles than in other groups with IL28B major allele. Treatment strategy should be carefully implemented in patients with IL28B unfavorable type.

Peginterferon/ribavirin effective for children, adolescents with chronic HCV
Treatment of chronic hepatitis C with pegylated interferon and ribavirin is effective and relatively safe for children and adolescents, according to recent results. Researchers performed a systematic review and meta-analysis of eight trials assessing the use of pegylated interferon (PEG-IFN) alfa-2a or 2b with ribavirin (RBV) in patients aged 3 to 18 years with chronic HCV.

 

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All Updates: HCV In Elderly Patients
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Abstract: A pilot study of triple therapy with telaprevir, peginterferon and ribavirin for elderly patients with genotype 1 chronic hepatitis C.
Results suggest that 24-week triple therapy with telaprevir 1,500 mg seems safe and efficacious for elderly Japanese patients infected with HCV genotype 1b.....

Abstract: Various Predictors of Sustained Virologic Response in Different Age Groups of Patients With Genotype-1 Chronic Hepatitis C.
SVR rate was highest in patients younger than 45 years and lowest in patients older than 65 years even through propensity score matching analysis. As for the SVR predictors ....

 

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All Updates: Liver Health Articles and Research
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Liver Transplant Houston: Is There a Special Diet to Follow?
A common question I am asked daily is in regard to “what kind of diet do I need to be on while waiting for my liver  transplant?”. There is a great deal of misunderstanding surrounding this, that it deserves a few simple comments.

Fat in Liver, Muscle, and Blood Increases Osteoporosis Risk
A new US study has revealed that, in addition to excess stomach fat, high fat levels in the liver and blood are also dangerous. The study, which was published in "Radiology", showed that people with higher levels of fat in their liver, muscle tissue and blood also have higher amounts of fat in their bone marrow, which increases the risk for osteoporosis.

Miriam A. Bredella from the Harvard Medical School in Boston and her team used proton magnetic resonance spectroscopy (MRS) to examine 106 men and women, aged 19 to 45 years, who were obese based on body mass index measurements, but otherwise healthy.

The researchers discovered that people with more liver and muscle fat had higher levels of fat in their bone marrow, independent of body mass index, age and exercise status. HDL cholesterol, the "good" type of cholesterol, was inversely associated with bone marrow fat content. Triglyceride levels had a positive correlation with bone marrow fat.

"Obesity was once thought to be protective against bone loss. We have found that this is not true," said Bredella. "If you have a spine that's filled with fat, it's not going to be as strong."
Article Source
Study available @ Medscape

Binge eating has scarred my liver
By Claire Bates BBC Science
When actor Ricky Grover, 51, was asked to take part in a TV programme testing for three serious health conditions he had no qualms in signing up. And tests revealed Mr Grover was showing signs of two of them. A skin-prick test revealed he had Type 2 diabetes while an MRI scan showed scarring, known as fibrosis, on his liver.....

FDA Voice -Reminds Consumers to Use Acetaminophen Safely
To help avoid the risk of liver damage, make sure you understand the information provided on the medicine label or the directions given by your health care professional....

Cutting Back on Fat and Sugar (In the Diabetic Liver)
In a way, the diabetic liver is like a lot of us—too in love with fat and sugar. In type 2 diabetes, the liver floods the bloodstream with three times more glucose than does a healthy liver, while at the same time storing more and more fat that can lead to chronic liver disease, cirrhosis, and liver cancer.

Eating Raw Oysters - Vibrio Vulnificus Bacteria Lurks In Gulf Waters
Those with liver damage due to excessive drinking and individuals with liver disease, including Hepatitis C and cirrhosis, are most at risk for developing serious illness from Vibrio vulnificus

Video
Hepatitis A and Hepatitis B Vaccine: Dr. Joe Galati Explains
Viral hepatitis most common causes of both cirrhosis and liver cancer 

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All Updates: 2013-Hepatitis C Full Text Articles
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Management algorithm for genotype 1 hepatitis C virus
Hepatitis C virus (HCV) infection is the most common etiology of chronic liver disease in Western countries. Morbidity and mortality due to HCV-related end-stage liver disease are increasing, just as novel therapeutics arrive with the promise of better cure rates that prevent these complications.
However, substantial barriers to successful application of these novel treatments remain, including the lack of providers with sufficient knowledge to address this epidemic. To address these deficits, this article aims to provide a general framework with algorithms to guide initial management decisions for HCV genotype 1 infection, the most commonly found genotype, based on therapies approved as of 2013.

Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function

Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives

Of Interest
Management of Treatment-Naïve Genotypes 2 and 3 HCV Infection

Advanced fibrosis is not a negative pretreatment predictive factor for genotype 2 or 3 chronic hepatitis C patients

Aust Fam Physician - Hepatitis C - An update

Durability of SVR in HCV patients treated with peg/riba and a direct-acting anti-viral
To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals.

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All Updates: Chronic hepatitis C: Treat or wait?
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Not Waiting for New Hepatitis C Treatment
by Lucinda Porter, RN on July 18, 2013 With new hepatitis C medications in the pipeline, I’ve heard people wonder if everyone should wait, or if there are reasons why patients might want to start treatment now. Here are some reasons why patients are starting treatment now, rather than waiting .....

Video Vignettes -Current Outlook On Hepatitis C Treatment
With rapid advancements in the field and new agents offering potential improvements in outcomes, shorter treatment durations, and unique adverse event profiles, clinicians must stay informed of the evolving data in order to counsel patients appropriately--in particular, those who may wish to discuss the benefits and risks of initiating therapy now vs delaying treatment. This program will consist of a series of four video vignettes presenting interviews with clinical experts who will explore some of the most pressing issues in the management of patients with HCV.

Janssen’s Simeprevir: Hep C Patients Hope It Is Worth the Wait
Simeprevir, a protease inhibitor developed by Janssen and Medivir, is 1 of the prospective agents that has been creating a stir in the HCV community The FDA recently granted the drug priority review, which may accelerate its journey to market and help close the treatment gap for patients in need. Janssen is seeking approval for simeprevir administered once daily along with pegylated interferon and ribavirin to treat adult patients with genotype 1 chronic
HCV with compensated liver disease.

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All Updates: Interferon Free Combinations
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Interferon-free Regimen for Hepatitis C Advances
The direct-acting antiviral combination, manufactured by AbbVie Pharmaceuticals, consists of the proteaseinhibitor ABT-450, the non-nucleoside NS5B polymerase inhibitor ABT-333, and the novel NS5A inhibitorABT-267. When used in combination with ribavirin, it reportedly produces sustained virologic response ratesof up to 99% in patients with hepatitis C.

Treatment Action Group 2013 Pipeline Report
"An impressive 26  new HCV drugs are being studied in phases II/III in at least28 interferon-free regimens, which are bringing the potential of  faster, all-oral HCVcures rapidly toward approval for the world’s 185 million people living with  HCV"

A brighter future in the fight against hepatitis  An interferon-free therapy for hepatitis C may also soon exist. In April, a triple combination of direct-acting antivirals without interferon showed efficacy in treatment-naive individuals and in nonresponders to standard of care

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All Updates: 2013 Stem Cell News and Research
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Perspectives on human micro-liver-like structures made from iPS cells

A Science First: Japanese researchers grow human liver using stem cells

Don’t market stem-cell products ahead of proof

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All Updates: HCV Triple-therapy Side Effects
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Renal impairment is frequent in chronic hepatitis C patients  under triple therapy with telaprevir or boceprevir

Health-related QOL poorer during early HCV treatment with addition of telaprevir

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All Updates: Drug To Drug Interactions in Triple Therapy 
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Meeting Report - 8th Hepatitis Pharmacology Workshop

There were several presentations in Wednesday’s session on drug interactions with new HCV agents in development and one survey on drug interactions with the currently licensed DAAs, boceprevir and telaprevir.

 

New HCV protease inhibitors interact with a wide range of drugs used in treatment of psychiatric conditions

A  review of data from clinical trials indicated that the anti-HCV protease inhibitors telaprevir (Incivek or Incivo) and boceprevir  (Victrelis) did not add to the psychiatric adverse-event profile of  existing HCV therapy. However, the investigators identified several significant interactions between the protease inhibitors and a number of antidepressants, benzodiazepines, anticonvulsants and antipsychotics. 

Drug interactions may compromise response to boceprevir and telaprevir
Concurrent use of drugs that alter concentrations of boceprevir (Victrelis) or telaprevir (Incivek or Incivo) in the body may contribute to poor response to interferon-based triple therapy for chronic hepatitis C virus (HCV), according to study findings presented at the Digestive Disease Week meeting (DDW 2013) last month in Orlando.

Few Quick Links - News Updates
News/Incivek (Telaprevir)
News/Victrelis (Boceprevir)
Sofosbuvir (GS-7977 and PSI-7977)
News/Fibrosis
News/Cirrhosis
News/Transplant
News/Liver Cancer