Baby Shroomers and the Heroin Spike: 6 Surprising Trends in Americans’ Drug Use

A new national study found drug use among those aged 50 to 64 has roughly doubled in the last few years, as has the number of people using heroin. Here's why

By Nate Rawlings @naterawlings Sept. 06, 2013

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The most comprehensive study of who’s using what in the U.S. came out on Wednesday. Here are six noteworthy stats from the federal government’s annual National Survey on Drug Use and Health of 70,000 Americans.

The methamphetamine epidemic is waning. The number of meth users in 2012 fell to 440,000, down from 731,000 in 2006. The Substance Abuse and Mental Health Administration, which conducted the survey, attributed the drop to states restricting the sale of key ingredients, like pseudoephedrine, which is found in cold medicines such as Sudafed.

(MORE: Thai Dealers Push Candy-Flavored Methamphetamine on Kids Outside Schools)

But heroin use is exploding. Between 2007 and 2012, the number of Americans shooting up nearly doubled, from 373,000 to 669,000. According to Mark Kleiman, professor of public policy at UCLA’s Luskin School of Public Affairs, that estimate may be low. Many heroin users are incarcerated, homeless, or not in a place where surveys can find them.

With cities and states cracking down on “pill mills”—illegal sources for Oxycontin and other prescription opiates—addicts are looking to get their fix elsewhere. “The prescription opioids are an easy path,” Kleiman says. “Then once people are strung out, they’ll do lots of stuff that they wouldn’t have done before.”

Pot is only getting more popular. Marijuana has long been the most commonly used drug in America, but its fan base is reaching new highs. In 2012, 18.9 million people used marijuana–7.3% of the population–up from 14.5 million in 2007. The number of daily users, now 7.6 million Americans, is growing as well.

Some of that rise likely resulted from growing acceptance of the drug—20 states and Washington, D.C. allow medical use, and Colorado and Washington State recently legalized recreational toking. “It’s clear that people are more willing to use legal than illegal drugs,” says Keith Humphreys, a psychologist and behavioral sciences professor at Stanford who served as a policy advisor at the White House Office of National Drug Control Policy.

The spirit of the ‘60s lives on. Here’s one statistic that will probably surprise people but shouldn’t: drug use among older people is way up. Last year, 7.2% of adults age 50 to 64 got high, up from 3.4 percent a decade ago. Among those aged 55 to 59, the drug use rate more than tripled, from 1.9% to 6.6%.

(MORE: Concert Deaths: Four Myths About the Drug Molly)

But those increases are mostly attributable to Baby Boomers getting older. “This cohort, particularly those born after 1950, had much higher rates of illicit drug use as teenagers and young adults than older cohorts,” the survey explains. “This generational shift in drug use is still evident in the most recent data.”

One of your neighbors is probably a binge drinker. Last year, 52.1% of Americans, 135.5 million people, reported drinking alcohol. Nearly one quarter, about 60 million people, were binge drinkers, which the study classified as having five or more drinks in the same occasion on at least one day during the month before being surveyed.

Teens don’t think smoking is cool anymore. 70 million Americans used tobacco last year, but fewer teens are lighting up. Over the last decade, tobacco use among teenagers (12 to 17-year-olds) dropped by nearly half, from 15.2% to 8.6%.

They’re still experimenting with alcohol though. Of the 4.1 million people who reported having their first drink in 2012, more than 80 percent were under the age of 21. You can’t win them all.

Source

Clinical Presentation, Outcome, and Response to Therapy Among Patients With Acute Exacerbation of Chronic Hepatitis C

Clinical Gastroenterology and Hepatology
Volume 11, Issue 9 , Pages 1174-1180.e11, September 2013

Evangelista Sagnelli, Mariantonietta Pisaturo, Maria Stanzione, Vincenzo Messina, Loredana Alessio, Caterina Sagnelli, Mario Starace, Giuseppe Pasquale, Nicola Coppola

published online 15 April 2013.

Abstract

Background & Aims

The slow asymptomatic progression of chronic hepatitis C (CHC) can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of CHC.

Methods

We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of CHC from January 2005 through June 2010; we followed them up for a median period of 36 months. These cases were hepatitis C virus (HCV) RNA positive, hepatitis B surface antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed up for at least 2 years. Liver biopsy specimens had been taken from 23 cases and 31 controls—once before enrollment in the study and once during the follow-up period.

Results

HCV genotype 2 was detected in 46.4% of cases, and HCV genotype 1 was detected in 43.9%. Among cases, the mean ALT level was 1063 ± 1038 IU/dL, and the mean total bilirubin level was 15.87 ± 7.15 mg/dL. A higher percentage of cases carried the interleukin-28B CC genotype than controls (40.2% vs 24.4%; P < .05). Among cases, 43.5% had a steady increase in ALT level (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsy specimens, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by more than 2 (P < .005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necroinflammation of more than 2 points (P < .005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained virologic response was achieved in 26 cases (81.2%) and 23 controls (60.5%).

Conclusions

Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a sustained virologic response after treatment with pegylated interferon and ribavirin.

Keywords: Hepatic Flare , Cirrhosis , Response to Therapy , Complication

Abbreviations used in this paper: ALT, alanine aminotransferase, AST, aspartate aminotransferase, CHC, chronic hepatitis C, HAI, Histologic Activity Index, HAV, hepatitis A virus, HBsAg, hepatitis B surface antigen, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HDV, hepatitis D virus, HEV, hepatitis E virus, IL, interleukin, LB, liver biopsy, peg-IFN, pegylated interferon, SVR, sustained virologic response

Conflicts of interest The authors disclose no conflicts.

Funding This study was supported by a grant from Progetti di Ricerca di Interesse Nazionale (PRIN) 2008, Ministero dell'Istruzione e dell'Università e della Ricerca Scientifica, Rome, Italy “Ottimizzazione Della Diagnosi Eziologica dell'epatite Acuta C E Studio dei Fattori Viro-Immunologici di Guarigione, di Cronicizzazione E di Risposta Alla Terapia Con Interferone,” and in part by a grant from Regione Campania “Progetti per il miglioramento della qualità dell'assistenza, diagnosi e terapia del paziente affetto da AIDS nei settori: immunologia, coinfezioni, informazione e prevenzione,” 2008.

PII: S1542-3565(13)00466-7

doi:10.1016/j.cgh.2013.03.025

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

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

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

Review

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

Keywords: Alcohol; viral hepatitis; liver; oxidative stress; free radicals; CYP2E1

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.

Conflict of interests

The author does not have any conflicting interests to declare.

References

Source

Update on epidemiology of hepatitis B and C in China

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 7–10, August 2013

Review

Yan Cui, Jidong Jia^*

Article first published online: 15 JUL 2013

DOI: 10.1111/jgh.12220

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

Keywords: China; epidemiology; genotype; hepatitis B; hepatitis C

Abstract

A high rate of chronic hepatitis B virus (HBV) infection in China is mainly caused by perinatal or early childhood transmission. Administration of universal HBV vaccination in infants has led to a dramatic decrease in HBV epidemiology, with hepatitis B surface antigen (HBsAg) prevalence declining from 9.75% in 1992 to 7.18% in 2006. The major HBV genotypes are B and C, with B being more prevalent in the southern part and C more prevalent in the northern part of China. A national survey carried out in 1992 showed that the hepatitis C virus (HCV) infection rate was 3.20% in general population in China. After implementation of mandatory HCV screening for blood transfusion and other precautions to prevent blood-borne disease since 1993, the new cases of HCV infection associated with blood or blood product has become very rare. Although the anti-HCV prevalence would be much higher in high-risk groups, a survey carried in 2006 showed that the anti-HCV prevalence rate was only 0.43% in general population. This sharp decline in HCV infection rate was mainly due to stringent administration and monitoring of blood donors and blood products, but may also be related to the remarkably improved specificity of anti-HCV test. The predominant HCV genotype in China is genotype 1b (60–70%), and the host interleukin-28b rs12979860 CC genotype is very frequent in Chinese population (over 80%).

Chronic infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) poses serious public health problems because of the high prevalence rates in many parts of the world and adverse long-term clinical outcomes, including premature deaths from hepatic decompensation, cirrhosis, and hepatocellular carcinoma (HCC). This is particularly true in China, where the prevalence rates of HBV and HCV infection were considerably high. Fortunately, thanks to the universal HBV vaccination program in infants and mandatory HCV screening in blood donors, and other precautions to prevent blood-borne diseases in health-care settings, the landscape of HBV and HCV epidemiology infection has changed greatly. In this short review, we will provide an update on epidemiology of HBV and HCV infection in mainland China.

Epidemiology of chronic HBV infection in China

Epidemiology of chronic HBV infection before introduction of universal HBV vaccination in neonates

China used to be a high endemic area of hepatitis B. A nationwide HBV sero-epidemiological survey conducted in 1992 showed that the HBsAg carrier rate in the whole population was 9.75%.[1] The HBsAg positive rate in the age group of 1–4 years already reached the level of the general population, suggesting that perinatal or early childhood acquisition of HBV may play a major role in chronic infection. It is estimated that 120 million people carried HBsAg, and around 300 000 of them died annually of liver cirrhosis and HCC.

Epidemiology of chronic HBV infection after introduction of universal HBV vaccination in neonates

After realizing that mother-to-child transmission was a major route and a leading cause of a high rate of chronicity of HBV infection in China, the government initiated universal HBV immunization program in 1992. Then, the government decided to integrate HBV vaccination into the Expanded Programme on Immunization and offer free vaccine for all neonates (a small amount of service fee was charged from their families) in 2002. Later, the government started to offer completely free HBV vaccination for all newborns in 2005.[2] All of these efforts have made the HBV vaccination coverage rate (including full three-dose immunization and timely first dose) in children increase steadily from about 30% in 1992 to near 90% in 2005.[3] Of note is that by the end of 2005, the vaccination coverage rate of HBV in rural was still 20% lower than that in urban area. However, in recent years, the gap on HBV vaccination coverage rates between urban and rural has been narrowing down.[4]

With the increasing coverage of HBV vaccination in infants, the HBsAg carrier rate in the vaccinated group (1.1%) has dramatically declined as compared with control group (15.8%), giving a protective efficacy of 93.0% (95% confidence interval [CI]: 92.1–94.0%).[5-7] The prevalence of anti-HBs was higher in fully immunized children (63.2–74.3%) than non-immunized children (21.1–34.8%).[4] A recent study on the infants immunized with plasma-derived HBV vaccine showed that although the anti-HBs positive rate and its titer decreased with time, the average HBV carrier rate of 1.6% did not increase during the 15 years after vaccination.[7] These data indicate that HBV vaccination not only reduces the HBsAg prevalence in early years but also possesses long-term immunity against HBV infection.

To evaluate the overall efficacy of HBV immunization, another nationwide HBV sero-epidemiological survey was conducted in 2006.[8] A total of 81 775 individual serum samples were collected at 160 disease surveillance sites from 31 provinces. To minimize bias, a multistage, cluster-randomized sampling from both rural and suburban was adapted in this survey. The result showed that the HBsAg carrier rate among aged 1–60 was 7.18% in 2006, giving an approximately one quarter declining from 9.75% in 1992.[8] Of note is that the HBsAg prevalence reduced remarkably among children aged < 15 years, especially among those aged < 5 years who have a prevalence of HBsAg less than 1.0%.[8] Therefore, HBV infection in China now should be changed from a high endemic area (with HBsAg prevalence in general population > 8%) to an intermediate endemic area (with HBsAg prevalence in the general population of 2–8%).

However, in China, the prevalence of HBV infection in some high-risk groups may still be much higher than that in the whole population. For example, the pooled prevalence of chronic HBV infection among hemodialysis patients was 11.9%.[9] Similarly, the overall prevalence of HBsAg was 12.49% (95% CI: 11.50–13.48) in HIV-positive patients, with needle sharing and unprotected sexual exposures being the major modes of HBV transmission in this special population.[10]

As chronic HBV infection is a major cause of cirrhosis and HCC, it is not surprising that HBV vaccination will also reduce the morbidity and mortality of these HBV-associated liver diseases. A study carried out in Long-an County, Guangxi Zhuang Autonomous Region in China showed that the HCC mortality among children aged 1–10 years old who had an HBV vaccination coverage of 89.9% was 0.4/100 000, which is remarkably lower than that in a control cohort born before the introduction of HBV vaccination program (5.7/100 000).[11] These data suggest that HBV vaccine administration in infants not only prevents HBV infection, but also reduces the morbidity and mortality of HBV-associated liver diseases, including HCC.

Molecular epidemiology of HBV in China

Whereas genotypes A and D are rare in China, genotype B and C are predominant, with more genotype B in the southern part and more C in the northern part of the country. In some regions of northern China, sub-genotype C2 is predominant, whereas sub-genotype C1 is more prevalent than C2 in southern China.[12-18] In western China, besides HBV sub-genotypes C1 and C2, the high prevalence of CD1 and CD2 was also found in Tibetan population, indicating that the distribution of these two sub-genotypes may be related to ethnic origin.[19] Compared with genotype B, HBV genotype C exhibits less replication activity in young patients but harbors higher frequencies of HCC-associated mutations.[20]

Epidemiology of hepatitis C in China

Changing epidemiology of chronic hepatitis C in China

China was considered a relatively high endemic area of HCV infection in the past. According to a national epidemiological survey carried out in 1992, the prevalence of anti-HCV averaged 3.2% in the general population, with blood or blood product transfusion as a major route of infection.[1] Since 1993, mandatory screening for anti-HCV before blood donation has been implemented. In addition, safe injection and other precautions to prevent blood-borne disease transmission have also been reinforced. Rewardingly, new cases of hepatitis C due to recent blood transfusion or invasive medical procedures have declined dramatically. As shown by a new national survey in 2006, the prevalence rate of anti-HCV is only 0.43% in mainland China.[21] The prevalence of HCV infection varies across different regions of China: the prevalence in northern area (0.53%) is higher than that in southern area (0.29%), but there is no statistically significant difference on anti-HCV prevalence across the eastern (0.37%), middle (0.67%), and western (0.31%) regions.[21]

No doubt this sharp decline in the prevalence of anti-HCV in China was mainly due to the implementation of stringent and effective precautions to control the HCV transmission in blood or blood product transfusion and other health-care settings. However, there are other possible explanations for this quick change in HCV epidemiology. One possible explanation is that the third generation of anti-HCV test used in the new survey in 2006 had a much better specificity than the first-generation test used in the first survey in 1992, therefore yielding much fewer false positive results. Another explanation was that the people at risk for HCV infection were underrepresented in the sample population. Indeed, some studies have identified a much higher prevalence of anti-HCV in high-risk groups, such as paid blood donors, patients on hemodialysis, patients with hemophilia, injection drug users (IDUs), men who have sex with men, and those with multiple sex partners. According to a meta-analysis,[22] the pooled prevalence of HCV infection among all blood donors in mainland China from 1990 to 2010 was 8.68% (95% CI: 8.01–9.39%). HCV infection rate in paid blood donors (15.53%, 95% CI: 13.28–17.91%) was significantly higher than that in voluntary blood donors (0.97%, 95% CI: 0.79–1.16%).[23] The prevalence of HCV infection in patients on maintenance hemodialysis in China was 41.1% (95% CI: 39.5–42.6%).[23] Furthermore, hemodialysis patients with blood transfusion were 5.65 times more likely to be infected with HCV than hemodialysis patients without blood transfusion.[24] The pooled prevalence of HCV infection among IDUs in China was 61.4% (95% CI: 55.7–67.2%), and the epidemic was most severe in provinces/autonomous regions likes Hubei, Yunnan, Guangxi, Hunan, and Xinjiang.[25] Due to shared risk factors for transmission, co-infection of HIV and HCV is common, especially among IDUs.[26] Several sero-epidemiological surveys revealed that the prevalence of co-infection of HCV in patients with HIV infection was 41.83–87%[10, 27-30]

Taking the above considerations into account, it is estimated by some experts that the “true” prevalence of anti-HCV may be around 1% in China.

Molecular epidemiology of HCV and host interleukin-28b (IL-28b) polymorphisms in China

The genotypes of HCV in China include four major genotypes and nine subtypes. The predominant HCV genotype in China is genotype 1 (69.6%),[31] with type lb in particular (accounting for 68.38%), followed by 2a (19.46%). Less common genotypes of 3b and 6 (mainly 6a) were seen mainly in the southern provinces. The HCV genotype 6 infection in Han Chinese is mainly found in the southern and western China, and the patients are usually younger than those with HCV genotype 1 infection.[32] Whereas subtype 1b strains are more likely associated with transmission via blood transfusion and medical procedures, subtype 6a strains are more likely linked to IDU and sexual transmission.[33]

In 2009, three genome-wide association studies reported that single nucleotide polymorphisms near IL-28B gene region were identified to be associated with the treatment efficacy of pegylated-interferon-α and ribavirin (peg-IFN-α/RBV) in HCV-infected patients.[34-36] The IL-28B gene allele frequency was reported to vary according to ethnicity. Liao et al. demonstrated that the rs12979860 C allele frequency is higher in Chinese patients than that reported in Caucasian patients.[37] This global difference of allele frequency may explain why Chinese patients respond better to peg-IFN-α/RBV therapy. Recently, Wei et al. and Ju et al. presented that the major genotype of HCV is 1b (around 60–70%), and the predominant host IL28b genotype of rs12979860 is CC (84%) in two large cohorts of Chinese HCV patients.[38, 39]

In summary, the prevalence of HBV and HCV infections used to be high in China. Introduction of universal HBV vaccination in neonates and the implementation of mandatory HCV screening for blood donors have achieved a great success in reducing the number of new cases of HBV and HCV infection during the last two decades.

Acknowledgment

This work was supported by the Beijing Municipal Science & Technology Commission (D121100003912003) and Major State Basic Research Development Program (2013ZX10002004-001-001; 2013ZX10002004-002-002).

Conflict of interests

The authors do not have any conflicting interests to declare.

References

Source

FDA rewrites opioid narcotic labels to tighten use for pain

The FDA has revised the labels of long-acting and extended-release narcotic pain relievers to indicate they are for patients with round-the-clock pain relief needs not met by other means. (Rich Pedroncelli / Associated Press)

By Melissa Healy

September 10, 2013, 1:27 p.m.

Patients should not be prescribed long-acting or extended-release opioid pain relievers unless they need daily, round-the-clock treatment of their pain that can’t be managed by any other means, the Food and Drug Administration has told physicians.

The new guidelines are to be included on the labels and patient information sheets of all prescription opioid pain relievers that dissolve slowly after taken.

Along with a call for new research aimed at identifying what doses and modes of use are most likely to harm patients, the revised labels are the latest step taken by the agency to stem a growing epidemic of opioid abuse and addiction in the United States.

They were announced Tuesday by FDA Commissioner Margaret Hamburg and the Obama administration’s drug czar, Gil Kerlikowske.

In redrafting the medications’ “indications for use,” the FDA aims to change the current practice of prescribing these powerful analgesics for use by patients on an “as needed” basis.

The new guidelines will not place formal new restrictions on prescriptions by physicians who treat patients for pain, but administration officials announcing the change made clear they hope to chasten physicians who prescribe the medications for anything other than ongoing, intractable pain.

Currently, the nonbinding physician prescribing guidelines issued by the FDA indicate that long-acting and extended-release opioid narcotics should be used for “moderate-to-severe” pain. The revision made by the FDA would not just remove “moderate pain” from the agency’s list of approved uses for the medications: It aims to get patients and their physicians to focus not only on levels of pain, but on how long it can be expected to persist and what alternatives exist to relieve it.

“The goal here was to make every patient taking extended-release and long-acting opioids to have a conversation about whether these products are helping them as individuals,” said Dr. Douglas Throckmorton, deputy director for regulatory programs at the FDA’s Center for Drug Evaluation and Research. “I hope this encourages physicians and patients to be more thoughtful and more careful as they use these medications.”

Physicians legally retain their broad latitude to prescribe long-acting and extended-release opioid narcotics “off-label” to patients when they judge such use to be medically warranted.

The FDA’s action does not change the labels or prescribing guidelines of fast-acting opioid pain relievers, which are often prescribed to patients following surgery or injury. Agency officials said they acted first to encourage more careful use of the long-acting and extended-release formulations because they pose a higher risk of abuse, addiction and overdose for patients.

The new steps come against the backdrop of opioid abuse and misuse that has been termed “epidemic” by the Centers for Disease Control and Prevention. In 2010, more than 12 million Americans reported they had taken opioid narcotics for purposes other than those approved by the FDA.

In 2008, deaths from opioid abuse overtook those associated with cocaine and heroin combined, reaching 14,800. In 2009, the misuse and abuse of prescription painkillers accounted for approximately 475,000 emergency department visits in the United States, a near doubling of such cases over 2004.

Officials said they have seen a sharp increase as well in the numbers of babies born in the United States who have been exposed to opioid painkillers in utero -- a condition that can result in painful and potentially life-threatening withdrawal symptoms in the early days of life.

The changes ordered by the FDA also encourage physicians to discuss the potential dangers of opioid medications to an unborn child when dealing with women of childbearing age.

Source

Conatus Pharmaceuticals' Emricasan Dosed in First Patient in Mayo Clinic Phase 2 Trial in Severe Alcoholic Hepatitis Population

SAN DIEGO, Sept. 10, 2013 (GLOBE NEWSWIRE) -- Conatus Pharmaceuticals (Nasdaq:CNAT), a biotechnology company focused on the development and commercialization of novel medicines to treat liver disease, today announced initiation of dosing in the Phase 2 clinical trial of emricasan in patients with severe alcoholic hepatitis. This study is being conducted by the Translational Research and Evolving Alcoholic Hepatitis Treatment (TREAT) Consortium consisting of the Mayo Clinic Rochester, Indiana University, and Virginia Commonwealth University in collaboration with the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

"We are very excited by this trial initiation of emricasan in patients with severe alcoholic hepatitis," said Steven J. Mento, Ph.D., President and Chief Executive Officer of Conatus. "We are developing emricasan as a first-in-class orally active treatment for chronic liver disease and acute exacerbations of chronic liver disease. Due to emricasan's mechanism of action and the presence of apoptosis and inflammation in many liver diseases, we believe there may be several patient populations that could potentially benefit from emricasan and have designed a comprehensive clinical program to demonstrate the therapeutic benefit of emricasan across the spectrum of fibrotic liver disease."

The trial is a placebo-controlled, double-blind, multicenter study that is designed to assess whether emricasan improves the 28-day survival in patients with chronic liver disease caused by alcohol and contraindicated to receive corticosteroid therapy for their alcoholic hepatitis. The study is designed to also evaluate the role of apoptosis and sterile necrosis in alcoholic hepatitis, the safety and tolerability of emricasan, overall clinical outcomes, and pharmacokinetics in this patient population.

"We are looking forward to studying the potential beneficial effects of emricasan in patients afflicted by this severe disease," said Vijay Shah, M.D., a hepatologist and principal investigator with the Mayo Clinic Rochester. "Alcohol-related liver disease is a major cause of morbidity and mortality in the U.S. and excessive alcohol consumption is the third leading preventable cause of death in the U.S."

Alcoholic liver disease encompasses a clinical/histological spectrum of disease including fatty liver, alcoholic hepatitis, and cirrhosis. Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. Severely affected patients show signs of retaining large amounts of fluid in the abdominal cavity (ascites), as well as kidney and liver failure. For additional information about the Phase 2 trial, please visit www.clinicaltrials.gov.

About Conatus Pharmaceuticals Inc.

Conatus is a biotechnology company focused on the development and commercialization of novel medicines to treat liver disease. Conatus is developing its lead compound, emricasan, for the treatment of patients in orphan populations with chronic liver disease and acute exacerbations of chronic liver disease. Emricasan is a first-in-class, orally active caspase protease inhibitor designed to reduce the activity of enzymes that mediate inflammation and cell death, or apoptosis. Conatus believes that by reducing the activity of these enzymes, emricasan has the potential to interrupt the progression of liver disease. For additional information, please visit www.conatuspharma.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release, including statements regarding the potential beneficial effects and development potential of emricasan, are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including Conatus' reliance on third parties to conduct its clinical trials, manufacture its preclinical and clinical drug supplies and manufacture commercial supplies of emricasan, if approved; potential adverse side effects or other safety risks associated with emricasan that could delay or preclude its approval; Conatus' ability to fully comply with numerous federal, state and local laws and regulatory requirements applicable to it; and those described in Conatus' prior press releases and the periodic reports it files with the Securities and Exchange Commission. The events and circumstances reflected in Conatus' forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, Conatus does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.

CONTACT: Paul Cox, Stern Investor Relations 
         (212) 362-1200, ir@conatuspharma.com 

Source

The first inpatient program to treat internet addiction has opened

Four beds ready to treat Internet addicts

By Ben Tinker, CNN

updated 7:10 AM EDT, Sat September 7, 2013

The majority of Internet addicts are consumed by playing games, experts say.

(CNN) -- High above the frozen Potomac River in the nation's capitol, Ryan Van Cleave stood on the Arlington Memorial Bridge, contemplating his life. It was New Year's Eve 2007, and the married father of two asked himself, "Is this really something I'm thinking about? Is my life really this out of control?"

At the precise moment he decided not to jump, Van Cleave slipped on a patch of ice and nearly fell to his death, 100 feet below. Then he took a deep breath and stepped back from the edge.

Van Cleave, an accomplished writer and college professor, had been laid off by his prestigious university as he descended into the depths of Internet addiction. He was playing online games for up to 80 hours a week. He was avoiding his real-life friends and ignoring his wife.

"I got so far into it," he says, "I couldn't realize how I got there."

Like many others who say they are addicted to the Internet, Van Cleave likens his addiction to alcoholism.

"A beer a day becomes a case a day," he says. "You can't stop, no matter how much you want to."

"The real problem," Van Cleave adds, "is that most people laugh at you and don't consider it a serious thing."

That sentiment could change on Monday, when the country's first inpatient treatment program for Internet addiction opens at Bradford Regional Medical Center in Pennsylvania.

"I've been studying Internet addiction since 1994," says Dr. Kimberly Young, a professor at St. Bonaventure University and the psychologist who founded the program at Bradford Regional. "When you talk about the controversy behind it, laughing it off, that's often been the case with my work."

The program is designed to accommodate four patients at a time, who all begin and end their treatment on the same day. The addicts' 10-day stay begins with a 72-hour "digital detox," followed by a full psychological evaluation.

Young and Dr. Roger Laroche, the medical director of Bradford Regional's Psychiatry department, expect to see withdrawal symptoms in their patients similar to those seen in hardcore drug addicts. Some, they say, will need to be medicated to make it through the detox.

"We're really behind other countries in treating this problem," says Young. "China, Korea and Taiwan all have treatment centers. Here in the United States, people who need treatment don't have anywhere to go. Now, we finally have something to offer people."

Because Internet addiction is not classified as a mental illness in the American Psychiatric Association's Diagnostic and Statistical Manual (often referred to as the "psych bible"), none of the program's $14,000 cost will be covered by insurance.

Dr. Allen Frances, the chairman of the DSM-IV and professor emeritus at Duke University, says there's little doubt that some people could indeed suffer from an Internet addiction. But he believes the research is premature.

"The concern is that there will not be a clear, bright line in between a true Internet addiction and the rest of us, who are using it recreationally," he says.

"People can spend 10 hours a day in front of a screen, blow off their wives, blow off their work, but that doesn't necessarily mean they're addicted," says Frances. "Addiction implies a pattern of use that you can't stop." The compulsion continues, even though time spent online is no longer productive or enjoyable.

Some studies show that the same areas of the brain that light up when alcohol and drug addicts get their fix light up when Internet addicts log on. An addict, by nature, is seeking a rush of dopamine, the neurotransmitter that is associated with feelings of reward and pleasure.

"That is a very critical aspect, as far as what separates addiction from just a bad habit," says Laroche. "We literally are talking about someone who has jeopardized his life and every aspect of it."

Dig deeper into the new Diagnostic and Statistical Manual, the DSM-V, and you'll find an entry for "gaming disorder" in Section III, meaning the American Psychiatric Association believes the condition warrants further research before it can be formally classified as a mental disorder.

Most Internet addicts, it seems, are plagued by an addiction to online games, more so than other online activities such as looking at porn, shopping or using social media.

Such was the case for Van Cleave who chronicled his experience in "Unplugged: My Journey into the Dark World of Video Game Addiction."

Van Cleave began gaming when he was a child.

"At college," he says, "I suddenly had a lot of unsupervised time. I started gaming exponentially more. If you don't study much, you have even more free time."

Eventually, Van Cleave reached a "crisis point," buried for up to 80 hours a week in World of Warcraft (a role-playing game in which you can "join thousands of mighty heroes in an online world of magic and limitless adventure.")

Van Cleave lost his job, some friends, and was barely able to save his marriage. "I pushed it awfully close to the line by not being available for a long time," he says.

"It was so obvious these things were happening, but I couldn't see it because I was knee-deep in the problem."

The foreword for Van Cleave's book was written by Dr. Mark Griffiths, a professor at Nottingham Trent University in the United Kingdom, who studies behavioral addictions in the School of Social Sciences. He says Internet addiction has five key criteria:

1. Salience: The Internet becomes the most important activity in the person's life, affecting feelings, behaviors and thoughts.

2. Mood modification: The person receives an emotional "buzz" from using the Internet.

3. Tolerance: The person becomes acclimatized, requiring increasing amounts of Internet time to get that "buzz."

4. Withdrawal symptoms: Abruptly ceasing Internet activity can cause the personal emotional or physical distress.

5. Relapse: The addict tends to fall back into the same behavior very easily, even after years of abstinence or control.

"When you see that behavior," says another recovering addict, Kevin Roberts, "it's only the tip of the iceberg. You're often going to find underlying issues."

In Roberts' case, the underlying mental health issues turned out to be ADHD and anxiety, which both went undiagnosed until his Internet addiction spun out of control.

It was good friends who had been through AA, dealing with addiction themselves, who recognized Roberts' categorical consumption with gaming had reached addictive proportions.

Unlike van Cleave, Roberts went on binges.

"I would go through periods when I wouldn't indulge," he says. Other times, he would play real-time strategy games for weeks at a time, at least eight to 12 hours a day. These binges were usually set off by an emotional trigger. "I would often be sleep-deprived, sometimes going a whole day or two without sleeping."

Roberts likened himself to a functional drunk.

"I held a job and paid my bills," he says. "I wasn't real successful at relationships, because of 'the screen,' but I didn't know that at the time."

While he was able to keep it together for a while, thanks in part to his being self-employed, Roberts eventually began to lose clients.

"I even lost money after performing work for someone," he says, "because I was too busy gaming to send out an invoice."

He lost standing in his profession that he may never gain back.

"I eventually stopped gaming," Roberts says, "because the thrill became less and less, even as I played more and more."

He and Van Cleave are among the minority of Internet addicts, experts say, who have been able to break their bad habits without an extreme intervention.

Roberts wrote a book about his experience, "Cyber Junkie: Escaping the Gaming and Internet Trap." Perhaps more importantly, he joined a cyberaddiction support group. "We're always there for each other," he says. "It's our 'Vitamin C,' C being for community."

It's that sense of camaraderie that Young hopes to evoke from her patients at Bradford General. "There's a group dynamic in having them be in a class together," she says. "There's a support system that builds up."

It's worth noting that reSTART, the country's first retreat center program for Internet addiction, opened in 2009. A 45-day retreat to "disconnect and find yourself" at reSTART costs $22,000, after which patients have the option to extend their retreat for $421 a day, depending on their individual treatment needs.

Van Cleave underscores the importance of getting professional help and learning, quite simply, how to properly think and function again in daily life. "Alcoholics can stay out of bars and restaurants that serve booze, but an Internet addiction is like an eating disorder," he says.

"They have to relearn how to eat, what foods to avoid, what stores to avoid," says Laroche, employing the same metaphor.

But Frances is worried a treatment regimen that could and should be applied to tens of thousands of people will instead be applied to millions. "I'm concerned there's so much publicity about these four lousy beds," he says. "This is being commercialized prematurely."

"Before developing clinical programs, we should have the research," says Frances. "This is a dangerous sign of a fad diagnosis. Unfortunately, the history of psychology is a history of fads like this."

"Remember," counters Young, "when Betty Ford first admitted she was an alcoholic, we didn't have people believing it was actually a problem until she came around and talked about her own problems with it. This is a place for people to go for help, and that we hope will help everyone around them stop taking Internet addiction so lightly."

Source

New study shines light on fight against hepatitis C and hepatitis B

Provided by Vaccine News Daily

Published on September 9, 2013 by Emma Rogers

A new study published online in the August 26 issue of Proceedings of the National Academy of Sciences gives insight on how to overcome autoimmune deficiencies caused by hepatitis C and hepatitis B.

The study was conducted by research teams at the Research Institute at Nationwide Children’s Hospital and Emory University. The study sought to discover if blocking a protein that helps hepatitis C control T cell function in the body would restore immune function, allowing it to fight off the hepatitis C infection.

The researchers based the experiment on programmed cell death 1, which tells T cells when to turn off and has been proven to shrink tumors in humans. PD-1 is the antibody that becomes controlled by hepatitis C during an infection, leading to the T cell exhaustion that makes T cells unable to fight off infection.

In the study, researchers gave animals with persistent HCV infection multiple doses of an anti-PD-1 antibody. The response among the animals was mixed, but did suggest that the amount of HCV-specific T cells in the liver at the time of treatment changes the efficacy of the treatment.

“Our supposition is that these T cells remained in the liver for years at levels too low to detect before treatment, and had the capacity to expand after treatment,” Dr. Christopher Walker, a senior author on the study, said. “The animal that responded to therapy had a broad, strong response during the early acute phase of infection. This suggests that one predictor of response to an anti-PD-1 antibody is the quality of the T-cell response when the initial infection occurs.”

The findings suggest the anti PD-1 antibody may be more effective against chronic hepatitis B infection. Research will commence in the near future to study the antibody’s effect on hepatitis B and the role of T cell immunity.

Source

Also See: Study Examines Ways to Restore Immunity to Chronic Hepatitis C Infection