INTIMP-03497; No of Pages 10 International Immunopharmacology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp

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Review

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Reshmi Chatterjee a, Abhisek Mitra b,⁎ a

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Article history: Received 8 October 2014 Received in revised form 12 December 2014 Accepted 14 December 2014 Available online xxxx

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Keywords: HBV HCV HCC Therapy Biomarker Clinical trials

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E.S.I. Hospital, Belur, West Bengal, India University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Chronic liver diseases (CLDs) such as hepatitis, alcoholic liver disease, nonalcoholic fatty liver, and their downstream effect cancer affect more than a billion of people around the world both symptomatically and asymptomatically. The major limitation for early detection and suitable medical management of CLDs and liver cancer is either the absent of symptoms or their similar manifestations as other diseases. This detection impediment has led to a steady increase in the number of people suffering from CLDs with an ultimate outcome of liver failure and undergoing transplantation. A better understanding of CLD pathogenesis has helped us to develop novel therapies for patients who are at greatest risk for CLD progression to the most serious disease cancer. With the discovery of aberrant molecular pathways in CLDs, it is now possible to delineate a road map for selecting targeted therapies for CLDs. Technological advances in imaging as well as the availability of several stable, sensitive, early, noninvasive biomarkers for distinguishing different stages of CLDs and cancer have greatly facilitated both drug target identification and real-time monitoring of response to therapy. Biomarkers are the most useful in clinical practice for liver diseases like hepatocellular carcinoma (HCC), which is associated with secretion of various tumor-related proteins or nucleotides in peripheral circulation. The need for the identification of CLD biomarkers remains high. This article reviews the etiologies of CLDs, the results of recent clinical trials of treatments for CLDs, and development of noninvasive methodologies for detecting CLDs and monitoring their progression toward HCC. © 2014 Elsevier B.V. All rights reserved.

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An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer

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Introduction . . . . . . . . . . . . . . . . Types of CLDs and associated HCC . . . . . . 2.1. Viral hepatitis . . . . . . . . . . . . 2.2. Nonalcoholic fatty liver disease (NAFLD) 2.3. Alcoholic liver disease (ALD) . . . . . 2.4. Hepatocellular carcinoma (HCC) . . . Treatment of CLDs and HCC . . . . . . . . . 3.1. Treatment for viral hepatitis . . . . . 3.2. Treatment for NAFLD . . . . . . . . 3.3. Treatment for ALD . . . . . . . . . . 3.4. Treatment for HCC . . . . . . . . . Novel non-invasive biomarkers . . . . . . . 4.1. Serum markers . . . . . . . . . . . 4.2. Circulating tumor cells (CTCs) . . . . 4.3. Novel protein markers for HCC . . . . 4.4. Circulating microRNAs (miRNAs) . . .

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Abbreviations: CLD, Chronic liver disease; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HBsAg, Hepatitis B surface antigen; HBeAg, Hepatitis B early antigen; NAFLD, Nonalcoholic liver disease; NASH, Nonalcoholic steatohepatitis; ALD, Alcoholic liver disease; HCC, Hepatocellular carcinoma; MAPK, Mitogen activated protein kinase; TGFβ, Transforming growth factor β; ALT, Alanine transaminase; AST, Aspartate aminotransferase; CTC, Circulating tumor cells; miRNA, MicroRNA; MRE, Magnetic resonance elastography; TE, Transient elastography ⁎ Corresponding author at: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel.: +1 713 563 0440; fax: +1 713 534 5871. E-mail address: [email protected] (A. Mitra).

http://dx.doi.org/10.1016/j.intimp.2014.12.024 1567-5769/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Chatterjee R, Mitra A, An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.12.024

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R. Chatterjee, A. Mitra / International Immunopharmacology xxx (2014) xxx–xxx

4.5. Circulating microparticles . 4.6. Novel imaging technologies 5. Conclusion . . . . . . . . . . . References . . . . . . . . . . . . .

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2.1. Viral hepatitis

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Hepatitis viruses have a special tropism toward hepatocytes and an ability to cause both acute and chronic liver diseases. There are 5 different hepatitis viruses from A to E of which predominantly B and C are causing CLDs and HCC. According to World Health Organization data, more than 5 million people in the United States and 500 million people worldwide are chronically infected with a hepatitis virus. A recent study predicted that the percentage of cirrhosis patients who are infected with hepatitis C virus (HCV) is likely to increase from 25% (of 3.5 million patients with cirrhosis) to 45% by 2030 [1]. On the basis of significant advances in our understanding of the life cycles of hepatitis B virus (HBV) and HCV (Fig. 1A), the chronic infection stage of these viruses can be divided into three stages: high immunological tolerance, immune competence, and immune control. Immunological tolerance is characterized by lack of symptoms; normal liver function; in HBV infection, high levels of hepatitis B surface antigen (HBsAg) and hepatitis B envelope antigen (HBeAg) in serum, which reduce helper T responses; and in HCV infection, PD-1 expression,

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2.2. Nonalcoholic fatty liver disease (NAFLD)

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NAFLD is a broad spectrum of diseases ranging from simple benign steatosis to nonalcoholic steatohepatitis (NASH) to progressive fibrosis, which can lead to cryptogenic cirrhosis and HCC. Sedentary lifestyles, poor food habits, and silent progression have contributed to the fatty liver disease epidemic in the Western world, affecting at least 25% of Americans [10]. The incidence of NAFLD has steadily increased from 57.5% to 74% in obese individuals [11]. Due to exponential growth of NAFLD, NASH is predicted to be the principal cause of cirrhosis and liver transplantation by 2020 [12]. The histological phenotypes of NASH are virtually indistinguishable from those of alcoholic steatohepatitis, which affected 6 million Americans according to a World Gastroenterology Organization report [13]. In 30–40% of NASH cases, the disease progresses to fibrosis, and in 10–15% of the cases, it progresses to cirrhosis [14]. The accumulation of fat in the liver can be mediated by several mechanisms, including lipolysis of adipose tissue, increased hepatic lipogenesis, and reduced secretion of low-density lipoprotein [15] (Fig. 1B). The risk factors associated with the transition from NAFLD to NASH have not been precisely identified; however, a multifactorial model has been proposed [16]. According to this model, pathological characteristics similar to those associated with NASH can be stemmed from different factors, including dietary intake of cholesterol [17], endotoxemia [15], interference with intestinal microbiota, Toll-like receptor 5 deficiency [18], hypoadiponectinemia [19], and endoplasmic reticulum stress due to exposure of hepatocytes to toxic lipids [20]. In a recent preclinical model showed that hepatic NKT cells are critical regulator of fibrogenesis in NASH by activating hedgehog signaling pathway to promote HSCs to stimulate pro-fibrogenic factor osetopontin [21] (Fig. 1B). Given these observations, progression to NASH is associated with lipid accumulation and inflammation in the liver.

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2.3. Alcoholic liver disease (ALD)

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ALD is a leading cause of liver disease-related mortality, causing 287,365 deaths in a 24-year-period in the United States [22]. ALDrelated mortality accounts for 40% of cases of cirrhosis and 28% of all liver disease-related deaths [22]. Among individuals who over a period of more than 20 years consumed on average 70 12-oz beers with 4% alcohol content per week or 70 1.5-oz glasses of wine with 11% alcohol content per week, 19% developed ALD and 7% of those with ALD developed cirrhosis [23]. From a histological perspective, ALD encompasses a broad spectrum of phenotypes, including steatosis, steatohepatitis, alcoholic hepatitis, cirrhosis, and HCC [24]. ALD-related liver injury involves acetaldehyde formation, glutathione depletion, increased lipogenesis resulting from increased

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The liver is the principal detoxifying organ and is actively involved in clearing pathogens, toxic chemicals, and metabolic waste products from the body to maintain homeostasis. Continuous exposure of the liver to viruses, excessive alcohol consumption, excessive fat accumulation, biotransformed metabolites, and cholestasis can cause hepatic injury, which can lead to inflammation and liver degeneration. When the injury sustains for a long time, it can cause CLDs, which occur in multistage processes of fibrosis, cirrhosis, and HCC. As the diseases progress to chronic stage, there is infiltration of polymorphonuclear leukocytes into the liver, with focal or zonal necrosis, destruction of hepatocytes, and architectural disarray. According to American Liver Foundation data, approximately 30 million Americans have been affected by liver and biliary diseases. In 2007, according to data from the Centers for Disease Control and Prevention, CLDs, cirrhosis and HCC were among the top 15 leading causes of death in the United States, and in 2010 alone, 31,802 people died of liver-related disease excluding 18,910 deaths from liver cancer. Patients with alcohol-related cirrhosis account for half of all hospital admissions associated with liver cirrhosis. It is now recognized that the increasing incidence of CLDs is associated with not only cirrhosis or HCC but also systemic impairments such as chronic fatigue, non-encephalopathyrelated cognitive impairment, vasomotor disturbances, and sleep disturbances. The major cause of liver disease progression to chronic stage or early stage of cancer is the absence of or minimal clinical manifestation. Thus, failure of patients to recognize symptoms of liver diseases during acute stage is a substantial risk related to death from CLDs. It is important to increase awareness especially among people associated with liverrelated disorders for a periodic monitoring in clinics. In the last decade, both therapeutically and noninvasive detection methods for CLDs have significantly improved. This article provides an overview of current concepts in CLD and HCC epidemiology, molecular pathways, therapeutic strategies and noninvasive biomarkers for diagnosing and monitoring disease progression.

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which exhausts CD8 T cells [2–4]. In addition, HCV-specific interleukin 10-producing CD8 T cells greatly facilitate progression to chronic phase in minimal necroinflammatory liver diseases [5, 6]. During the immune competence phase, hepatocytes are infected via low-density lipoprotein receptor [7], and immune activity commences. The immune active phase of chronic HCV infection is associated with HCV-specific T cells and intrahepatic lymphocytes at a higher frequency in the liver than in peripheral circulation [8, 9]. Infiltration by immune cells and subsequent eradication of HCV-infected hepatocytes constitute the major mechanism of protecting the liver from viral pathogens.

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Please cite this article as: Chatterjee R, Mitra A, An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.12.024

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permeabilization of intestine, which increases fatty acid uptake by the liver from adipose tissue, and inhibition of β-oxidation of fatty acids as a result of an increased NADH/NAD ratio in hepatocytes [24] (Fig. 1C). Chronic alcohol consumption leads to activation of the innate immune system, especially Kupffer cells, which secrete proinflammatory cytokines like tumor necrosis factor-α, and it can lead to liver injury by recruiting lymphocytes.

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2.4. Hepatocellular carcinoma (HCC)

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HCC is the fifth leading cause of cancer and second leading cause of cancer-related death in the world [25, 26]. Approximately 700,000 new HCC cases are detected and more than 600,000 deaths are

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associated with HCC every year worldwide [27]. Approximately 75–80% of HCC frequently occurs in HBV- or HCV-infected individuals whose disease has progressed to chronic stage such as cirrhosis [28]. Extensive epidemiological studies revealed that liver carcinogenesis has very complex etiologies and, in addition to being associated with viral infection, it is linked with several other risk factors: foodstuffs containing aflatoxin B1, obesity, diabetes, alcohol consumption, and tobacco use. Furthermore, to understand the pathophysiology of HCC, it is important to study the cellular signaling pathways that play a critical role in the development and progression of liver cancer. Multiple signaling pathways undergo dysregulation in HCC: Wnt/βcatenin, p53, mitogen-activated protein kinase (MAPK), PI3K/AKT/ mTOR, and transforming growth factor β (TGFβ) (Fig. 1D) [29–34].

Please cite this article as: Chatterjee R, Mitra A, An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.12.024

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3.1. Treatment for viral hepatitis

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Treatment for chronic viral hepatitis continues to improve as new data on the viral life cycle inside the host emerge. In the case of HBV, many studies indicated that the ideal therapeutic approach would be aimed at completely suppressing HBV DNA rather than achieving HBeAg seroconversion, as HBV DNA is found in many patients [41, 42]. Based on success rates in clinical trials, seven drugs have been approved by the US Food and Drug Administration for treatment of viral hepatitis: peginterferon α-2a, interferon α-2b, lamivudine, adefovir, tenofovir, entecavir, telbivudine and clevudine. Interferon-α therapy is considered as the first approved treatment for chronic HBV infected patients with minimal chance to develop drug resistant strain. Compared with interferon α-2b, peginterferon α-2a was reported to have higher efficacy with a better pharmacokinetic profile, to elicit less drug resistance, and to require a less stringent dosing regimen [43]. Combination therapy with peginterferon α-2a and lamivudine, a nucleoside analogue, suppressed HBV DNA more effectively that peginterferon α-2a alone in a randomized clinical trial [44]. In a recent in vitro study showed that high dose of IFN-α or lymphotoxin β receptor activation upregulates APOBEC3A and APOBEC3B cytidine deaminases that causes degradation of covalently closed circular DNA of HBV to inhibit HBV reactivation.

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3.2. Treatment for NAFLD

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Fatty liver disease has a direct association with obesity, insulin resistance, type 2 diabetes, and dyslipidemia. Presently, lifestyle modifications like a low-carbohydrate diet and daily exercise are considered standard recommendations for reducing steatosis. However, many patients have difficulty adhering to food and exercise regimens. Alternatively, bariatric surgery has shown promising results in reducing steatosis in obese patients; however, postoperative complications such as bleeding, wound infection, anastomotic leak, thromboembolism, bowel obstruction, gallstones, and death limit the use of this approach [49]. Pharmacological agents can also be used to alleviate steatosis and NASH. In randomized clinical trials, vitamin E and the peroxisome proliferator-activated receptor gamma agonist pioglitazone, a thiazolidinedione, consistently demonstrated histological efficacy [50]. In one recent randomized clinical trial, patients receiving vitamin E showed significant improvement in a primary histological endpoint measure with reductions of at least 1 point in hepatocyte ballooning and 1 point in lobular inflammation or steatosis score in 43% of patients [51]. In another randomized clinical trial, pioglitazone treatment improved insulin sensitivity in hepatocytes, reduced inflammation, and resuscitate liver histology in 73% of patients [50]. Vitamin E is generally preferred over pioglitazone as it is safer, more cost-effective, and has fewer side effects. Metformin, pentoxifylline, statins, and incretin mimetics are also available for treatment of NAFLD; however, histological improvement, efficacy, and long-term safety need to be validated for these agents in large clinical studies.

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Treatment of patients with CLDs has been a big challenge for physicians because CLD is usually diagnosed at the irreversible-cirrhosis, cancer or liver failure stage. The considerable progress that has been achieved in well-performed translational studies suggests that significant improvement in treatment of CLDs may occur in the near future. Table 1 lists the results of the most recent clinical trials, and the various therapies currently used to treat CLDs and HCC are discussed in depth below.

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Despite its clinical success, peginterferon α-2a is not widely prescribed for HBV treatment due to HBV genotypic limitation (A and B). In contrast, numerous nucleoside analogues, such as lamivudine, adefovir, tenofovir, entecavir, and telbivudine, are widely used for long-term treatment of HBV infection, as these agents can inhibit virus replication and have excellent tolerance and safety profiles. Tenofovir, a reverse transcriptase inhibitor, is the latest drug approved by the US Food and Drug Administration for HBV treatment. Forty-eight weeks of tenofovir therapy showed promising results: viral suppression in 76% of patients, normalization of alanine transaminase in 68%, and HBsAg loss in 3.2% [45]. The efficacy of tenofovir is especially high in HBeAg-negative patients, with viral suppression observed in 93% of such patients in a phase III study [45]. Tenofovir can be considered the most potent medication against chronic HBV infection with no reported drug resistance. Treatment of chronic HCV infection improved significantly after the crystal structures of several HCV proteins were characterized. Triple therapy combining the protease inhibitor boceprevir or telaprevir with peginterferon-α and ribavirin achieved a sustained viral response in 59–69% of patients with chronic HCV infection [46]. Presently, a number of direct-acting antiviral agents targeting HCV RNA polymerase or nonstructural protein 5A and host-targeted compounds are under study. In 2014, there is a significant advancement in interferon or ribavirin free therapy for chronic HCV type I genotype which is affecting 70% of cases in the USA [47, 48]. FDA approved Harvoni (fixed combination of ledipasvir and sofosbuvir) and Olysio (simeprevir) for chronic HCV type I patients. An open-label study with 100 HCV infected patients were treated with fixed combination of ledipasvir and sofosbuvir alone for 8 or 12 weeks showed great potential to cure in 95% of the treated patients [47]. Similar promising result was obtained with a combination therapy of simeprevir and sofosbuvir in multi-center trials with 168 patients who had previously not responded to pegylated interferon and ribavirin. Based on 8 and 12 weeks of therapy, it showed high rates of SVR (95–100%) in patients even in those with compensated cirrhosis and non-responder to protease-inhibitor regimens. With fewer tolerable side effects and improved treatments, these emerging therapies have the potential to reduce HCV occurrence in high risk population.

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Several studies showed that inactivation of the β-catenin suppressor adenomatous polyposis coli, gain-of-function mutations in β-catenin, and mutations in the negative regulators of the Wnt pathway Axin1 and Axin2 were found in 50% of HCC patients [29]. As in other cancers, p53 protein undergoes alteration due to a spectrum of mutations in different positions between exons 4 and 9 [35]. The two most frequently occurring p53 mutations in HCC are a transversion caused by aflatoxin B1 at the third base in codon 249 and a transversion in codon 250 due to the effect of oxidative stress [29]. Mutations in the p53 gene cause genomic instability and abrogate the gene's regulatory role for proteins associated with the cell cycle, thereby increasing the chance of tumor development. Another important pathway, MAPK, which plays a critical role in cellular growth and differentiation, is constitutively activated in many HCC patients. The PI3K/AKT/mTOR signaling pathway can be considered another promising target in liver carcinogenesis, given that it has been reported to undergo aberrant activation in 48% of HCC patients [36]. The mutation at Akt S473, the most frequent HCC-associated mutation in this pathway (found in 71% of HCC patients), promotes invasion, metastasis, and vascularization in HCC tumors [37]. Alteration of the TGFβ signaling pathway has also been commonly observed in HCC progression, with overexpression of TGFβ and downregulation of TGFβ receptor II reported in 40% and 37–70% of HCC patient, respectively [38]. The tumorigenic role of TGFβ signaling is thought to occur through activation of the mitogenic Ras/Raf/MAPK pathway, which promotes cell proliferation independently of SMAD [39]. Furthermore, the TGFβ pathway plays a critical role in tumor invasion and metastasis by upregulating extracellular matrix proteins and decreasing the production of enzymes that degrade those proteins [40]. The TGFβ signaling pathway thus plays important roles in both the early and the late phases of liver carcinogenesis.

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Please cite this article as: Chatterjee R, Mitra A, An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.12.024

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R. Chatterjee, A. Mitra / International Immunopharmacology xxx (2014) xxx–xxx t1:1 t1:2

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Table 1 An overview of recently completed clinical trials for CLDs.

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Drug name

Type of CLD

Phase Outcome of trial of trial

Mechanism of action

References

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HBsAg–HBIG immunogenic complex therapeutic vaccine Besifovir HEPLISAV

HBV

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HBV HBV

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Modulation viral antigen processing and presentation Inhibitor of HBV polymerase HBV vaccine targets TLR9

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NASVAC

HBV

III

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Daclatasvir plus sofosbuvir

HCV

III

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HCV

III

HCV

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HCV protease inhibition and immune stimulation Vaccine targeting NS3, NS4 and NS5B of HCV Farnesoid X receptor agonist

[112]

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Simeprevir plus peg-interferon and ribavirin TG4040 plus peg-interferon and ribavirin FLINT

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Spironolactone and vitamin E

NAFLD II

[115]

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Phlebotomy

NAFLD II

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Obeticholic acid

NAFLD II

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Ezetimibe Cysteamine bitartrate

NAFLD II NAFLD IIb

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Pioglitazone

NASH

IV

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Liraglutide

NASH

II

Iron reduction and significant improvement in liver histology Decrease insulin resistance, liver inflammation and fibrosis. Ameliorate hepatic fibrosis Reduces ALT, AST values but no significant improvement in body mass index. Significant improvement from lobular inflammation, steatosis and necroinflammation. Well tolerated and improves liver histology

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Glucocorticoids and N-acetylcysteine

ALD

III

Improves 1 month survival of patients.

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X-linked inhibitor of apoptosis (XIAP) antisense AEG3515 and sorafenib Tivantinib Sorafenib and gemcitabine Sorafenib and tegafur/uracil MGN-3 with interventional therapy Pegylated arginine deaminase

HCC

II

More promising than sorafenib alone.

Improve insulin resistance in NAFLD patients Targeting iron overload to increase oxidative stress Farnesoid X receptor ligand to regulate glucose and lipid metabolism. Inhibition of cholesterol absorption Potent antioxidant to increase GSH production Decrease lipid accumulation and increase glucose uptake Glucagon-like-peptide-1 agonist to increase insulin secretion Inhibits AP-1 and NF-κB and anti-oxidant Multiple cellular pathway blocker

HCC HCC HCC HCC HCC

II II II II II

Potential alternative option for advanced HCC patients. Not better than sorafenib alone. More efficacious than sorafenib alone. Useful for the treatment of HCC. Promising and well tolerated.

t1:28

TRC105 anti-angiogenic monoclonal antibody 5-Fluorouracil/leucovorin (FOLFOX4)

HCC

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HCC

III

Well tolerated in patients. Suitable as a combination therapy. Increased response rate and median overall survival.

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NAFLD IIb

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Superior response compared to peg-interferon or ribavarin Decreases body weight, γ-glutamyl transpeptidase and NAS score Decrease in serum insulin and insulin-resistance

[109] Dynavax Technologies Vaccine comprises of HBsAg and HBcAg [110], to cause immunogenicity NCT01374308 NS5A inhibitor [111]

Oral inhibitor of MET Multiple cellular pathway blocker Multiple cellular pathway blocker Potent immune system booster Systemic deprivation of arginine in cancer cells Targeting CD105 to inhibit tumor angiogenesis. Cytotoxicity

[113] [114]

[116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130]

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R

t1:29

Complete seroconversion as early as in 30 days and seroprotection with highest α-HBs titer at day 90. High rate of SVR response among patients infected with HCV 1, 2, or 3 Well tolerated and high rate of SVR response

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t1:11

HBeAg seroconversion is decreased. Overdosing caused immune fatigue. Similar effect as entecavir. Complete seroprotection after three doses.

3.3. Treatment for ALD

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Successful strategies for management of ALD include medication, liver transplantation, behavioral therapy, and psychosocial assistance to facilitate complete abstinence from drinking. Primary medications approved by the US Food and Drug Administration for ALD are disulfiram (an inhibitor of alcohol dehydrogenase), acamprosate (an anticraving drug), baclofen (a γ-aminobutyric acid B receptor agonist), and naltrexone (an opioid antagonist). For alcoholic patients with hepatitis, corticosteroids, pentoxifylline, nutritional therapy, and liver transplantation are advised. Because of heterogeneity in clinical outcomes, especially in hepatotoxicity, for the various drug treatments for ALD, the search continues for new compounds and molecular targets. Chemokines, the extracellular matrix protein osteopontin, gut microbiota, endocannabinoid receptors, and the inflammasome are considered key targets for designing next-generation treatments for ALD. Besides medication, cognitive–behavioral therapies can provide selfmotivation for coping with the urge of binge drinking, analysis of situation, and skills for abstaining from alcohol. These nonmedicinal approaches offer highly structured instructions and assignments and include support of family members in directing patients toward healthy activities. Such modification of behaviors related to alcohol consumption can be a safer mode of treatment than medication.

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3.4. Treatment for HCC

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Selection of appropriate therapy for HCC should take into account tumor size and location, underlying liver function, the presence or absence of cirrhosis, and the physical status of the patient. Sorafenib, surgical resection, transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), ethanol ablation, combination therapy, and liver transplantation are the most common treatments for HCC. Sorafenib, a receptor tyrosine kinase inhibitor, showed promising results in patients with advanced HCC: the survival rate in those patients was 10.7 months, compared to 7.9 months for the placebo group [52]. In that clinical trial, drug-induced grade 3 toxic effects were reported in very few patients: diarrhea in 8% of the patients, hand-foot syndrome in 8%, hypertension in 2%, and abdominal pain in 1%. The authors of that study concluded that sorafenib alone or in combination can be effective against HCC patients [52]. Liver transplantation is considered the second-best option for treatment for HCC, as it has been reported to increase the patient survival rate by 67–91% [53]. The only drawbacks of liver transplantation are the need to administer immunosuppressive drugs, which might cause tumors to relapse, and the fact that only 5% of HCC patients are eligible for this procedure [54]. Another approach, surgical resection, can be used to remove a tumor along with surrounding hepatic tissue if the non-cirrhotic region is greater than 25% of the total

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4.1. Serum markers

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Serum markers that reflect hepatic dysfunction are referred to as indirect markers, whereas serum markers that predict changes in extracellular matrix turnover are referred to as direct markers. Potential indirect markers include alanine transaminase, aspartate aminotransferase, γ-glutamyl transpeptidase, total bilirubin, alkaline phosphatase, and albumin. As these substances leak from injured hepatocytes into the bloodstream, their levels in serum increase above the normal range. Hematological variables such as prothrombin index and platelet count are also considered indirect biomarkers of CLD. In contrast to indirect markers, direct biomarkers reflect modifications in molecular pathogenesis of fibrosis or metabolite levels. Direct markers proposed for detecting fibrosis include glycoproteins such as serum hyaluronate [59], laminin [60], and YKL-40 [61]; collagens such as procollagen III N-peptide [62] and type IV collagen [63]; and collagenases such as tissue inhibitor of metalloproteinase-1 [64] and matrix metalloproteinases, along with collagenase inhibitors [57]. Some of the recent studies provided a better understanding to state whether NAFLD can be considered as a potential risk factor for coronary artery diseases (CAD). Based on the serum concentrations of heat shock protein-70 (HSP-70) and gamma-glutamyl transferase (γ-GT), it can be stated NAFLD has insignificant role in determining CAD [65, 66]. However, circulating levels of HSP-70, γ-GT and Bcl-2 were elevated from lower to higher grades of steatosis. These markers could be utilized as potential tools to understand the progression of NAFLD [65–67]. In ALD, conventional biomarkers are not suitable for distinguishing alcohol-based liver toxic effects from coexisting causes of liver dysfunction. Researchers are also looking for serum markers that reveal information about recent drinking activity, termed state markers, and markers of genetic proclivity for alcohol dependence, termed trait markers [68]. With improvements in measuring techniques, carbohydrate-deficient transferrin, mean corpuscular volume, and N-acetyl-β-hexosaminidase have

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4.2. Circulating tumor cells (CTCs)

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Identification and quantitation of CTCs undoubtedly have significant clinical correlation with tumor aggressiveness, prediction of recurrence and monitoring response of patients toward treatment. The discovery of novel cell surface markers to detect these rare CTCs from peripheral blood of HCC patients is growing. In the past year, in 2013, epithelial cell adhesion molecule, asialoglycoprotein receptor and intracellular adhesion molecule 1 were proposed as novel markers of CTCs in HCC patients [26, 30, 77–80]. These novel CTC markers can potentially complement traditional methods of monitoring disease progression and predicting overall survival for HCC patients.

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4.3. Novel protein markers for HCC

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Alpha-fetoprotein has also been used as a serological biomarker of HCC. However, because of alpha-fetoprotein's poor detection sensitivity at the early stage of HCC and high serum levels in patients with nonmalignant CLD, alternative protein markers of HCC have been proposed. Sall4, Glypican-3, dickkopf-1 and talin-1 are promising candidates, having demonstrated greater sensitivity and specificity for CLD than has alpha-fetoprotein [32, 81–84]. These proteins are completely undetectable in sera of healthy individuals.

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4.4. Circulating microRNAs (miRNAs)

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Clinical correlation of response to treatment with disease progression is critical for proper assessment and management of CLDs and HCC. Liver biopsy-based histological studies aimed at determining the extent of architectural distortions in CLDs and HCC are considered the most predictive and specific indicator for selecting a treatment regimen. However, liver biopsy has a number of well-documented limitations. This invasive procedure can lead to bleeding and/or significant pain. It can produce a sampling error due to small specimen size. It can be expensive. It does not allow for dynamic evaluation over time. And different pathologists may interpret histological findings differently [56, 57]. Predictive noninvasive biomarkers have been proposed as an adjunct tool to be used with biopsies. Ideal noninvasive biomarkers for CLDs and HCC need to have high sensitivity, specificity, and reproducibility. They need to outperform traditional liver function tests, be easily detectable in both preclinical and clinical settings, and be correlated with histopathological characteristics of liver diseases [58]. Noninvasive biomarkers include serum markers and findings obtained with imaging techniques and transient elastography (TE). With the help of “omics” technologies such as genomics, proteomics, and metabolomics, research on serum biomarkers continues to advance toward the goal of clinically managing disease progression with greater sensitivity and specificity. With the large number of studies being conducted on serum biomarkers for CLDs and HCC, novel markers that have most of the desirable characteristics described above will likely be identified in the near future.

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shown promising sensitivities and specificities as state markers [68]. As trait markers, adenylyl cyclase activity [69], gamma-aminobutyric acid [70], dopamine receptor [71], β-endorphin [72], and serotonin transporter [73] have been reported to differentiate alcoholics and nonalcoholics. Furthermore metabolic byproducts of alcohol in the liver are considered as direct serum markers of CLD. These byproducts include acetaldehyde [68], ethyl glucuronide [74], ethyl sulfate [75], 5-hydroxytryptophol [76], dolichols [68], and salsolinol [68]. Usually, these markers have a halflife of only a few hours in biological fluids in cases of acute alcohol consumption; however, in habitual alcoholics, these markers have been detected from 24 h to a few days after alcohol consumption. Increasingly, metabolic products are gaining importance in diagnosis of CLDs because they are not subject to dissimulation by patients. Much attention in CLD serum marker research has focused on detection of disease at the asymptomatic stage and on monitoring disease progression. All noninvasive methodologies being developed have potential limitations, such as the fact that the most commonly used enzymes and proteins are not liver specific and the fact that the level of liver dysfunction has to be high for a marker of CLD to be detectable in serum. In addition, the rate of excretion may alter the concentration of direct-marker metabolic products in serum. In light of these important limitations, comprehensive metaanalyses of these biomarkers need to be conducted, and algorithms predicting clinical outcomes need to be developed. Of the several hundred serum markers of CLD available, none has been independently validated with optimal accuracy for early or longitudinal progression of disease. The diagnostic accuracy of a biomarker is measured as area under the receiver operating characteristic curve. Typically, the values near the ends of the area under the curve indicate either high sensitivity and low specificity or low sensitivity and high specificity, and these results are clinically meaningful for patient prognosis. However, results in the intermediate range, with moderate sensitivity and specificity, do not reliably indicate disease progression. Because of these shortcomings, researchers have created panels of different combinations of biochemical and clinical markers to integrate noninvasive and histopathological methods for diagnosis and treatment of CLDs.

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liver. The 5-year postoperative survival rate for HCC patients who undergo surgical resection is around 40–70%; however, the recurrence rate is almost 70% [31, 55]. Although these various treatment strategies for HCC have shown promise, large clinical trials are required to accurately ascertain recurrence and overall survival rates of patients.

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Extensive research on miRNAs has linked these small noncoding 485 RNA molecules to liver biology and hepatic dysfunction [85] and 486

Please cite this article as: Chatterjee R, Mitra A, An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.12.024

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Microparticles (MPs) are heterogeneous population of spherical structures with a size range between 100 and 1000 nm [33]. MPs are budding from the plasma membrane with known to express antigen from their parental cells. These are elevated in many disease states such as inflammation, auto immune disorders, malignancies, atherosclerosis, renal failure and numerous infections [34]. Recent studies illustrated that MPs can be considered as a non-invasive biomarker in acute liver failure, chronic hepatitis C and NAFLD where these showed correlation with the extent of histological inflammation in paired biopsies [89–92]. Presently, large number of patient screening and efficient enrichment technology are required to utilize it as universal marker for CLDs.

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4.6. Novel imaging technologies

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With the significant advances made in the past few decades, imaging technologies are gradually gaining prominence among clinical methods of diagnosing liver diseases. The transition from anatomical to molecular imaging has initiated a new era in noninvasive detection of liver diseases. The imaging methods most commonly used for liver disease are ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography, molecular imaging, transient elastography (TE), controlled attenuate parameter (CAP) and magnetic resonance elastography (MRE). Of the currently available imaging platforms, translational imaging technologies such as positron emission tomography, MRE, and TE are matching with the requirements of clinical needs. Molecular imaging can detect changes in expression of surface proteins on a cell and metabolic functions of inflammatory and tumor cells that might correlate with disease progression. With the availability of new molecular probes for inflammation and tumors, molecular imaging technologies have the potential to visualize, characterize, and offer greater diagnostic flexibility for clinical assessment of liver pathology [93–95]. Researchers are also investigating the plasticity of liver tissue in CLD progression. An active area of investigation is correlation of the degree of liver stiffness due to fibrosis with pathophysiological changes in liver tissue, as it is well known that the liver is stiff at the cirrhosis stage and HCC [96]. The contractile property of the liver has been utilized to measure shear elasticity by transmitting longitudinal waves. A study using a rodent model showed that liver stiffness begins much

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Table 2 Most commonly deregulated miRNAs in chronic liver diseases.

t2:1 t2:2

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493

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4.5. Circulating microparticles

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549 550

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510

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earlier than collagen deposition [97]. In this method, an ultrasound transducer probe emits a low-frequency (50 Hz) vibration that generates a shear wave and disseminates it into the liver [98]. The clinical accuracy of TE is particularly high in detecting progressive evolution of cirrhosis, for which the sensitivity of TE is greater than 90% [99]. The inter- and intra-observer variability of TE are minimal according to studies of cirrhosis and HCC patients. However, TE has several limitations. This technique is not suitable for detecting early and intermediate stages of fibrosis or measuring complex advanced portal hypertension [96]. In addition, TE is not recommended for obese patients (body mass index above 28 kg/m2) or patients with ascites or narrow intercostal spacing [100] or in case of extrahepatic cholestasis [101]. Due to potential limitations of TE, the recent imaging modality CAP has been utilized efficiently to detect fibrosis and different grades of steatosis [101]. It uses Fibroscan M probe to measure the ultrasound attenuation with values range from 100 to 400 dB/M for steatosis detection [102]. A recent study linking CAP values with steatosis grades (S1 to S3) among 135 patients revealed that it can differentiate more than two grades apart precisely compared to semi-quantitative grading and the sensitivity of this method varied between 73 and 83% and the specificity was 84–96% [103]. Supporting to these observations, a prospective study with more than 5300 examinations showed that technical failure of CAP was observed in only 7.7% of cases [101]. Another major finding in this study was a direct relationship between the mean CAP values with increasing number of alcohol drinks per week. With such a high accuracy, low sampling error rate and a clear diagnostic concept, CAP technology is a promising tool to characterize major histopathological aspects of patients with steatosis. Another elasticity-based imaging technique, MRE, is a threedimensional approach that can use the phase contrast method to visualize propagation of acoustic shear waves transmitted through the liver. The underlying theoretical principles of MRE and TE are similar, but MRE has several advantages over TE: a minimal sampling error rate, the ability to scan almost the whole liver using a three-dimensional displacement vector, and the ability of compression waves to penetrate throughout the liver (making MRE suitable for obese patients and patients with ascites). Furthermore, MRE has excellent sensitivity and specificity, with values above 85% for detecting hepatic fibrosis at stages 2 to 4, based on receiver operating characteristic curve analyses [98]. Over the years, MRE has gained significant importance as a tool for CLD diagnosis and treatment, particularly in helping to match hepatitis patients with appropriate therapy. Imaging evaluation for accurate assessment of response to therapy, recurrent and new tumors are essential for proper management of HCC patients. Based on technological advancements and upgraded algorithms, contrast-enhanced ultrasound (CE-US), multidetector computer tomography, nuclear medicine and MRI (gadolinium, diffusionweighted imaging, blood oxygen level dependent, perfusion-weighted imaging) are recently using for better correlation between hemodynamics and pathophysiology [104]. Size of liver nodules (either N2 or b2 cm) is an important aspect for specificity and sensitivity of the

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elucidated their roles in regulating lipid- and glucose-metabolizing enzymes, inflammation, fibrosis, and cancer-related signaling pathways in the liver (Table 2). Elevated levels of circulating miRNAs in serum are highly correlated with pathophysiological changes in inflammationmediated liver diseases. Usually, these extracellular miRNAs are detected in exosomes, microvesicles, or bound to proteins that facilitate extreme stability in acidic environments and RNase resistance. These properties can extend the half-lives of miRNAs by several days over the half-lives of markers in current clinical use. Numerous studies have suggested that elevated levels of miRNA-122 (miR-122) in serum are correlated with various CLDs such as HCV infection, NAFLD, NASH and ALD. Elevated serum levels of other extracellular miRNAs have also been linked to CLDs. miR-155, for example, was found to be elevated in both sera and peripheral monocytes of patients with chronic HCV infection [86]. In patients with chronic HCV infection or NAFLD, serum levels of miR-34a and miR-16 were correlated with disease severity [87]. In patients with cirrhosis, miR-513-3p and miR-571 serum levels were significantly higher than in control individuals [88]. Collectively, these findings suggest that circulating miRNAs may be more, sensitive and more specific than other serum markers for early detection of CLD and for gauging response to treatment. The levels of extracellular miRNAs in serum are much lower than in whole blood, and sophisticated instruments are required to obtain precise measurements.

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551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599

Circulating miRNAs

Liver diseases

References

t2:3

miR-16 miR-21 miR-34a miR-101 miR-122 miR-125b miR-155 miR-192 miR-194 miR-199 miR-223

HCC, HCV, HBV HCC, HCV HCC, NAFLD HCC, HBV HCC, ALD, HCV, HBV and NAFLD HCC, HCV, ALD HCC, ALD, HCV HCC, HCV, NAFLD HBV, HCV, HCC HCC, HCV, HCC, HBV

[87,131] [132,133] [134,135] [131,136] [131,133,137,138] [139–141] [141–143] [144,145,140] [131,146,147] [148,149] [133]

t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14

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References

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The considerable progress in our understanding of CLDs and HCC at both the molecular and the cellular levels has greatly facilitated the design of numerous drugs and combination therapies that may have clinical importance. Additional multicenter, long-term therapy with comprehensive clinical trials of novel agents and combination treatments are strongly recommended to avoid the potential relapse of CLDs and HCC. Noninvasive biomarkers for detecting and monitoring CLDs and HCC are becoming clinically valuable tools for assessing disease severity. The limitations associated with biomarkers are low sensitivity and specificity in disease staging. This improper assessment of CLDs could be a potential risk factor for disease progression to HCC. Clinical evidence suggests that combinations of biomarkers improve diagnosis and therapy of CLDs and HCC could be avoided. This review provides comprehensive information about the recent updates on therapeutic and diagnostic tools for proper management of patients affected with CLDs and its associated HCC.

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Dig Dis Sci 2005;50:171–80. [12] Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis—new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013;10:627–36. [13] Erickson SK. Nonalcoholic fatty liver disease. J Lipid Res 2009;50:S412–6 [Suppl.]. [14] M I, Singh C, Ganie MA, Alsayari K. NASH: the hepatic injury of metabolic syndrome: a brief update. Int J Health Sci (Qassim) 2009;3:265–70. [15] Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836–46. [16] Coulon S, Legry V, Heindryckx F, Van Steenkiste C, Casteleyn C, Olievier K, et al. Role of vascular endothelial growth factor in the pathophysiology of nonalcoholic steatohepatitis in two rodent models. Hepatology 2013;57:1793–805. [17] Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lutjohann D, et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 2008;48:474–86. [18] Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010;328:228–31. [19] Musso G, Gambino R, Biroli G, Carello M, Faga E, Pacini G, et al. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2005;100:2438–46. [20] Lee JS, Zheng Z, Mendez R, Ha SW, Xie Y, Zhang K. Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model. Toxicol Lett 2012;211:29–38. [21] Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, et al. NKTassociated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 2012;61:1323–9. [22] Paula H, Asrani SK, Boetticher NC, Pedersen R, Shah VH, Kim WR. Alcoholic liver disease-related mortality in the United States: 1980–2003. Am J Gastroenterol 2010;105:1782–7. [23] Huang YW, YSS, Kao JH. Pathogenesis and management of alcoholic liver cirrhosis: a review. Hepat Med Evid Res 2010;2011:1–11. [24] Orman ES, Odena G, Bataller R. Alcoholic liver disease: pathogenesis, management, and novel targets for therapy. J Gastroenterol Hepatol 2013;28(Suppl. 1):77–84. [25] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–43. [26] Mitra A, Satelli A, Xia X, Cutrera J, Lopa M, Li S. Cell-surface Vimentin (csVim): a mislocalized protein for isolating csVimentin CD133 novel stem-like hepatocellular carcinoma cells expressing EMT markers. Int J Cancer 2014. [27] Dhanasekaran R, Limaye A, Cabrera R. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepat Med 2012;4:19–37. [28] Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013;13:123–35. [29] Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008;48:2047–63. [30] Satelli A, Mitra A, Cutrera JJ, Devarie M, Xia X, Ingram DR, et al. Universal marker and detection tool for human sarcoma circulating tumor cells. Cancer Res 2014; 74:1645–50. [31] Mitra A, Satelli A, Yan J, Xueqing X, Gagea M, Hunter CA, et al. IL-30 (IL27p28) attenuates liver fibrosis through inducing NKG2D-rae1 interaction between NKT and activated hepatic stellate cells in mice. Hepatology 2014;60:2027–39. [32] Mitra A, Mishra L, Li S. Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol 2013;31:347–54. [33] Mitra A, Ross JA, Rodriguez G, Nagy ZS, Wilson HL, Kirken RA. 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imaging technologies to characterize arterial-phase hypervascularity and later washout. In case of nodule size above 2 cm, only a single imaging technique (CT or MRI) is needed to establish confidently its vascular characteristic profile [104]. However smaller lesions ranging from 1 to 2 cm show diagnostic challenges on imaging due to atypical vascularization and features of cirrhotic and dysplastic nodules [105, 106]. As per the guidelines of the American Association for the Study of Liver Diseases (AASLD), two coincident dynamic imaging modalities are required to diagnose malignancy in small neoplastic lesions. Contrary to this, Sangiovanni et al suggested sequential application rather than combined approach for imaging techniques to detect 1–2 cm nodules for improving sensitivity while maintaining high specificity. During HCC surveillance to identify 1–2 cm malignant tumors, single imaging technique was able to detect with 100% specificity and 66% sensitivity compared to 66% specificity and 34% sensitivity in combined procedures [106]. In another study published by Khalili et al, developed an algorithm to detect an additional 20% nodules with a sensitivity of 62%, specificity of 79% and a 73% save of liver biopsies to detect [107]. The authors suggested to use only fine-needle biopsy examination of indeterminate nodules showing either arterial hypervascularity on CT or MRI scan or the presence of a typical synchronous HCC [107]. In conclusion, biphasic combination of arterial phase hypervascularity and delayed phase hypovascularity are essential for the best sensitivity and specificity for diagnosing 1–2 cm HCC nodules with minimal exposure of radiation dose for patients who are likely to undergo multiple follow-up imaging studies. In light of the significant progress that has been made in the use of imaging technologies as noninvasive tools for diagnosing and monitoring CLDs and HCC, these technologies are likely to play an increasingly important role in routine clinical practices, with a potential to decrease the need for liver biopsies.

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Please cite this article as: Chatterjee R, Mitra A, An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.12.024

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