July 2014, Volume 10, Issue 7
Pejman G. Mansourian, MD, Masato Yoneda, MD, PhD, M. Krishna Rao, Fernando J. Martinez, MD, Emmanuel Thomas, MD, PhD, and Eugene R. Schiff, MD
Dr Mansourian, Dr Yoneda, and Mr Rao are clinical research fellows, Dr Martinez is a gastroenterology fellow, Dr Thomas is an assistant professor, and Dr Schiff is a professor and director of the Schiff Center for Liver Diseases at the University of Miami Miller School of Medicine in Miami, Florida.
Address correspondence to: Dr Emmanuel Thomas, 1500 NW 12th Avenue, Suite 1101, Miami, FL 33136, Tel: 305-243-2895, Fax: 305-243-5885, E-mail: EThomas1@med.miami.edu
Abstract: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer morbidity and mortality worldwide and is one of the few cancers that is increasing in incidence. This cancer often arises in the setting of hepatic cirrhosis; however, it can also occur in patients with chronic hepatitis B virus infection without cirrhosis. Statins have been used for many years for the prevention and treatment of cardiovascular disease. Based on recent meta-analyses, these lipid-lowering agents are now being investigated for a class effect observed in the prevention of carcinogenesis. There are robust data suggesting that statins can alter biochemical pathways involved in tumorigenesis and cell survival and, thus, have a protective effect by reducing the risk of development of several types of cancer. In recent years, several studies have demonstrated that statins also can specifically decrease the risk of HCC development. Because statins are underutilized in patients with preexisting liver disease, understanding the role of statins in the prevention of HCC is important, and changes in practice guidelines supporting the use of statins as chemoprotective agents may be warranted.
Hepatocellular carcinoma (HCC) often occurs in the setting of prior liver disease, such as in patients with hepatic cirrhosis and in chronic viral hepatitis. This cancer is frequently diagnosed in advanced stages. Affected patients have a median survival of 6 to 20 months.1 HCC results in 250,000 to 1,000,000 deaths per year and is the fifth and seventh most common cause of cancer worldwide in men and women, respectively. Additionally, large racial and ethnic disparities exist in both the incidence and clinical outcomes of HCC in the United States.2 HCC is the second most common cause of cancer-related death in men and the sixth in women.3 Known risk factors for HCC include hepatitis B virus (HBV) carrier state, chronic hepatitis C virus (HCV) infection, hereditary hemochromatosis, stage 4 primary biliary cirrhosis, alpha-1 antitrypsin deficiency, and cirrhosis of any etiology, including alcoholic hepatitis and nonalcoholic fatty liver disease (NAFLD).4
In the United States, the incidence of HCC increased more than 2-fold from 1985 to 2002. Although approximately half of this increase can be attributed to patients with chronic HCV infection, a significant portion of patients (>15%) have no clear viral or alcoholic etiology. NAFLD, obesity, and diabetes mellitus also may be important contributors to this increase in HCC.5 Interestingly, chronic HBV infection is strongly associated with the development of this malignancy, and HCC can develop in infected patients even if there are no signs of liver cirrhosis. Regardless of this observation, the majority of patients with HBV infection in whom HCC develops have evidence of cirrhosis.6 Other factors that increase the risk of development of HCC in patients with chronic HBV infection include viral load and the presence of hepatitis B surface antigen, indicating that active replication may drive tumor development.
Chronic HCV infection is also associated with HCC; however, affected patients almost exclusively have evidence of advanced liver fibrosis and cirrhosis. It is believed that HCC occurs in HCV-infected patients due to the rapid turnover of hepatocytes and inflammation caused by cytokine release. This leads to the survival of poorly differentiated hepatocytes, which proliferate and develop into dysplastic nodules that can subsequently develop into HCC.7
Recently, diabetes has been demonstrated to be an independent risk factor for HCC. A meta-analysis showed that persons with diabetes had a 2.31-fold increased risk for development of HCC and a 2.43-fold increased risk of HCC mortality compared with nondiabetic persons.8 In addition, a prospective study of 578,700 adults demonstrated that glucose levels were positively associated with the risk of HCC.9 This mechanism of HCC development that is associated with diabetes may be driven by nonalcoholic steatohepatitis (NASH) and can occur even in noncirrhotic patients10; however, there is evidence in the literature that this may not be a strong association.11,12
Current Surveillance and Therapeutic Strategies
Due to the aggressive nature of HCC, surveillance is needed to decrease mortality from the disease; thus, it is important to identify high-risk patients and provide adequate surveillance. The objective of HCC surveillance is to detect new tumors at the earliest possible time point to increase the chance of survival, or if this is not possible, should, at minimum, provide a meaningful improvement in survival duration.13 Surveillance is warranted in patients with HBV or HCV infection because their annual risk of HCC exceeds 0.2% and 1.5%, respectively.13 In addition, patients with HBV or HCV infection who are coinfected with HIV are at a higher risk for rapidly progressive cirrhosis and subsequently the development of HCC.14 Moreover, HCC in these patients is significantly more aggressive compared with HCC in patients infected with HBV or HCV alone.15-17 As discussed previously, patients with cirrhosis of any etiology are ultimately at a higher risk for the development of HCC.18 The current practice guidelines from the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Asian Pacific Association for the Study of the Liver recommend noncontrast enhanced ultrasound screening every 6 months for patients in these high-risk groups.13,19,20 Measurement of alpha-fetoprotein (AFP) levels is not recommended for surveillance or diagnosis due to poor sensitivity and specificity. In addition, the measurement of AFP is not cost-effective because it does not provide any additional value, unlike ultrasound surveillance.21,22 With regard to effectiveness, a population-based study in the United States revealed that 6.6% of 3903 Medicare patients with HCC received regular surveillance prior to diagnosis.23 This finding replicated the low rate of screening uptake (12%) among HCV-infected veterans with cirrhosis.24 Thus, although the benefits of surveillance for HCC are known by most physicians and patients, surveillance for HCC is still not common practice.25
For patients diagnosed with HCC, initial management involves staging the tumor using the Barcelona Clinic Liver Cancer staging system.26 HCC detected at early stages can be treated with curative procedures such as surgical resection, liver transplantation, and radiofrequency ablation. For intermediate and advanced cancers, treatment options include transarterial chemoembolization (TACE) alone or in combination with sorafenib (Nexavar, Bayer/Onyx), a kinase inhibitor. Patients who do not respond to TACE or who have more advanced HCC can be treated with sorafenib alone because its use has demonstrated a survival benefit.27,28 This drug targets tyrosine protein kinases, such as vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor receptor as well as rapidly accelerated fibrosarcoma (RAF) kinases and c-Kit receptors.29,30 Thus, this pharmacologic agent targets critical pathways involved in cell proliferation and survival.
Molecular Basis of Tumor Formation
The molecular pathogenesis of HCC is a complex process that involves the alterations of several regulators of the cell cycle. The most commonly involved genes are TP53 (25%-40%) and CTNNB1/β-catenin (26%, associated with chronic HCV infection), although many other candidate driver mutations have been documented.31 Important downstream effects of these mutations are seen on the signaling cascades of Ras and Rho (Figure 1) and epithelial growth factor receptor, which are activated in over 50% of cases.32 The tumor suppressor pathway involving the mammalian target of rapamycin is also often disrupted (40%-50%) in HCC.33
In addition, pathways involving angiogenesis have been shown to be of particular importance in HCC tumorigenesis due to the increased vascularity found in these tumors, and significant research efforts are ongoing to discover novel treatments that would inhibit the implicated molecular pathways.34 Another important player in hepatocarcinogenesis is the activation of the Myc transcription factor. Mitogenic signaling cascades, including those involving the Wnt, sonic hedgehog, and epidermal growth factor molecules, lead to activation of this protein. Subsequently, Myc activation causes several changes in cell growth regulation. By increasing the production of cyclins and downregulating p21, Myc activation causes an increase in uncontrolled cell growth. Activated Myc also can downregulate the antiapoptotic Bcl-2 protein, favoring cell survival and escape from programmed cell death. Moreover, cells with activated Myc have upregulated levels of ribosomal RNA and corresponding proteins that contribute to increased cell proliferation. Cumulatively, these molecular changes play an important role in the development, proliferation, and survival of cancer cells that are further illustrated by studies showing that Myc inactivation can induce HCC regression.35-37
Statins: Development, Use, and Adverse Events
In 1978, the first therapeutic statin molecule was isolated from Aspergillus terrus and was later marketed by Merck Research Laboratories as lovastatin.38 Since then, numerous clinical trials have provided a vast wealth of data on the safety and efficacy of these drugs. Statins belong to a class of drugs that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This inhibition causes a reduction in cholesterol production in hepatocytes due to decreased levels of mevalonate, an intermediate in the cholesterol synthesis pathway. There are robust data correlating increased cholesterol levels with the risk of cardiovascular disease and stroke; therefore, statins are useful in the prevention of these diseases and will be of increased importance as obesity rates increase.39 Clinical studies have demonstrated that statins are most effective for treating cardiovascular disease by secondary prevention.
An adverse effect of statin use that is of particular importance in the field of hepatology is the elevation of liver enzymes and possible liver injury, which has been deemed to be rare and unpredictable. Many healthcare providers continue to avoid statins in patients with chronic liver disease.40 However, recent studies have demonstrated the safety of statins in patients with chronic liver disease, with maintenance of the associated benefits of decreasing the risk of cardiovascular events.41 In general, statin toxicity seems to occur in less than 3% of all patients taking statins, and if toxicity is present, it also appears to be dose-dependent; however, many cases of statin toxicity spontaneously resolve.41 One of these studies included a prospective, randomized, double-blind, placebo-controlled trial that investigated the safety
As previously mentioned, attention has been focused on mevalonate production and downstream molecules that are inhibited by statins. GGPP and FPP are 2 such end products that are crucial for the proliferation of malignant cells. Their absence leads to apoptosis via activation of the Ras and Rho pathways.74-77 Statins also exert proapoptotic effects via a HMG-CoA reductase–dependent mechanism that activates caspases and decreases Bcl-2. This is mediated by regulating the RAF/mitogen-activated protein kinase 1 (MAPK)/extracellular signal-regulated kinase (ERK) pathway.78,79 Statins also inhibit the proteasome pathway; thus, GGPP and FPP escape inactivation by degradation and can exert their cell growth inhibitory effects in cancer cells.73,80 Additional mechanistic studies are needed to further investigate the mechanisms through which statins affect these pathways at the molecular level. Additional studies elucidating the possible mechanisms underlying the anti-HCC activity of statins may foster the use of statins in the treatment of HCC or enable the development of small molecules with more specific and potent anti-HCC activity.
Evidence for a Role of Statins in the Prevention of Hepatocellular Carcinoma: Laboratory and Epidemiologic Studies
In vivo, anticancer properties of statins were first suggested in 1996 when lovastatin induced a minor response lasting 8 months in a patient with anaplastic astrocytoma.81 Since then, multiple studies have been conducted with statins for both prevention and treatment of cancers with varying results. In 2011, a study was published demonstrating that inhibition of HMG-CoA reductase, with atorvastatin in HCC cell lines, resulted in Myc phosphorylation and activation subsequently suppressing tumor growth and antiapoptotic pathways.82 Another study showed that pitavastatin (Livalo, Kowa) can prevent liver tumorigenesis in obese mice, suggesting that statins may have a chemoprotective effect in obese persons.83
Amid the data showing the antitumorigenic effects of statins, interest has increased in recent years regarding the effects of statins on the risk of HCC, and several recent studies have shown that statins can have antineoplastic effects in HCC.84 A cohort study of 33,413 HBV-infected persons in Thailand demonstrated a significant dose-response relationship for HCC prevention in patients receiving statins. The hazard ratios for patients after receiving 28 to 90 cumulative defined daily doses (cDDDs) compared with no statin was 0.66 (95% CI, 0.44-0.99), suggesting a significant preventative effect of statins on the development of HCC in patients infected with HBV.85 Another cohort study of 260,864 patients with HCV infection, with a follow-up period of nearly 3 million person-years, demonstrated a reduced risk of HCC in HCV-infected patients taking statins. The adjusted hazard ratios were 0.66 (95% CI, 0.59-074) for those with 28 to 89 cDDDs, 0.47 (95% CI, 0.40-0.56) for those with 90 to 80 cDDDs per year, and 0.33 (95% CI, 0.25-0.42) for those treated with more than 180 cDDDs per year.86 Furthermore, usage of statins as adjuvant therapy along with standard chemotherapeutic regimens seems promising in prolonging survival. A treatment regimen utilizing pravastatin was shown to increase median survival rates in patients with advanced HCC from 8 to 16 months (P=.006) when combined with the standard treatment of 5-fluorouracil and transcatheter arterial embolization compared with patients receiving standard therapy alone.87 The Table lists the various studies that have demonstrated a reduced risk of HCC in patients treated with statins.51-53,85,86,88-92
Singh and colleagues conducted a systematic review and meta-analysis to investigate the effects of statin use and the risk of HCC.93 Seven observational studies and 3 studies reporting pooled data from 26 randomized controlled trials were included in the analyses. This comprehensive meta-analysis included data from more than 1.4 million patients with 4298 cases of HCC. The authors concluded that statin use was associated with a 37% reduction in the risk of HCC after adjusting for confounding variables. In this study, the effect on the incidence of HCC was greater among Asian populations compared with Western populations.93 This can be explained by the fact that most cases of HCC in Asia and Sub-Saharan Africa are caused by viral hepatitis. In particular, HBV genome integration can lead to DNA microdeletions in the host DNA, causing changes in cell growth regulation via pathways such as MAPK.94 In addition, the HBV X protein can upregulate various cell cycle control genes, such as Ras, Raf, MAPK, and ERK, leading to an increase in cell proliferation and survival.95,96
These changes may confer a growth advantage to neoplastic cells leading to the development of HCC in HBV-infected patients. As previously described, statins can inhibit these growth-promoting pathways and act as chemoprotective agents against liver tumorigenesis. In a similar manner, statins can inhibit the detrimental effects of HCV activation on the nuclear factor kB pathway, which causes inflammatory changes and immune activation leading to increased cell turnover, cirrhosis, and eventually malignant transformation.97 Moreover, HCV can promote cell growth by downregulating growth arrest and DNA damage repair genes, such as Gadd45.98 This can be countered by the antigrowth and apoptotic effects of statins.64 In contrast, the mechanism by which statins reduce the risk of HCC in Western populations is less clear. A significant number of HCC cases in the Western world are associated with NAFLD and metabolic syndrome. Thus, the protective effect of statins in this population seems to involve modification of the metabolic syndrome, insulin-mediated cell proliferation, and reduction of obesity-associated inflammation.93 Interestingly, a study by Tsan and colleagues in 2012 investigating the effects of statins on the risk of HCC in HBV-infected patients showed that risk reduction was independent of lipid-lowering effects, alluding to multiple mechanisms leading to antitumor activity.85
Shortcomings of the Currently Available Evidence and the Need for Future Studies
Although there is mounting evidence that statins have a chemoprotective effect on the prevention of HCC, several published studies examining this clinical outcome present conflicting results. In addition, it has been pointed out that selection or recall biases may play a role in the seemingly protective effect of statins in HCC prevention.84 In contrast to observational studies, several randomized controlled trials of statins for the prevention of HCC have failed to demonstrate a protective effect. Specifically, in a post hoc examination of 22 randomized controlled trials involving statin therapy (Cholesterol Treatment Trialists’ Collaboration), data from approximately 135,000 subjects yielded a total of 68 cases of HCC. It was concluded from this study that patients who were treated with statins were at equal risk for development of HCC compared with patients who were treated with placebo (adjusted odds ratio, 1.06; 95% CI, 0.66-1.71).92 In addition, with regard to other cancers, the use of statins has been significantly associated with an increased risk of tumor progression in patients with bladder cancer. In 53% of the patients who took statins and were followed for this cancer, tumors became more aggressive; however, this finding was observed in only 18% of patients who did not take statins (P=.004; odds ratio, 4.9; 95% CI, 1.64-14.69).99
Unfortunately, most randomized controlled trials involving statins were carried out to study cardiovascular endpoints, and there are several limitations when these studies are used to examine cancer-related outcomes. Specifically, with regard to observational studies, it is difficult to determine the right dose, frequency, duration, and even when to initiate statins for cancer chemoprevention. Furthermore, due to the moderately low occurrence of HCC in the general population, designing these randomized controlled trials is logistically difficult. In addition, when factors such as patient dropout and mortality risks due to cirrhosis are considered, the volume of patients required to carry out such chemoprevention testing becomes much higher than predicted. Moreover, due to the clear correlation between viral hepatitis and the development of HCC, the need to delay antiviral therapy to reduce confounding factors would be ethically challenging. Finally, as mentioned previously, the chemopreventive effect of statins on HCC in comparison to the effects of anti-HCV therapy is still not clear.100
To account for these issues, a more robust analysis is needed because many of the aforementioned studies looked at cancer as a secondary outcome or were performed in patients with advanced disease. Although statins may be safe in cirrhotic patients,101 this cohort requires increased attention for analysis of chemoprevention for HCC. Ultimately, large, properly planned cohort studies, with long and meticulous follow-up, on specific populations at increased risk for HCC would be more viable and better suited for the development of rigorous data to this end.
Conclusion
HCC is a major cause for cancer-related death worldwide, and early detection and treatment are extremely important for improving patient survival. Surveillance with semi-annual ultrasound screenings in high-risk patients is essential for early detection. However, decreasing the baseline risk of HCC development is paramount in improving survival of patients with chronic liver disease.
Statins have shown chemoprotective effects against several cancers, and their antiproliferative and apoptotic properties have been demonstrated in recent years. There is strong evidence that statin use in patients with chronic liver disease is safe and beneficial from a cardiovascular standpoint. Statin use in patients with chronic liver disease also has been associated with a reduced risk of development of HCC, although a precise mechanism that accounts for this reduction is lacking. In addition, adjuvant chemotherapy using a treatment regimen that includes a statin in patients with HCC is promising in prolonging survival.
Although a vast amount of data show the role of statins as chemoprotective agents, most of the studies have been observational and retrospective in nature. Therefore, there is a need for additional prospective cohorts and interventional studies to further support the role of statins in the prevention of liver tumorigenesis in humans as well as animal models. Moreover, continued research is warranted to elucidate the biochemical mechanisms of how statins affect the development of HCC. Future research should include substantiating the preventative role of statins in liver cancer so that the use of these drugs can be incorporated into current practice guidelines for the prevention and treatment of this aggressive cancer, especially in those with mild liver disease who may benefit the most from such therapeutic intervention.
The authors have no relevant conflicts of interest to disclose.
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