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Recent Insights Into the Relationship Between Inflammatory Liver Diseases and Atherosclerosis
  1. Tugrul Purnak, MD*,
  2. Cumali Efe, MD,
  3. Yavuz Beyazit, MD,
  4. Ersan Ozaslan, MD*,
  5. Ramazan Astan, MD§,
  6. Aysel Milanlıoglu, MD,
  7. Zeynep Ozbalkan, MD,
  8. Manfredi Rizzo, MD, PhD**
  1. From the *Department of Gastroenterology, Ankara Numune Education and Research Hospital; †Department of Gastroenterology, Hacettepe University School of Medicine; ‡Department of Gastroenterology, Yuksek Ihtisas Education and Research Hospital, Ankara; §Department of Cardiology, Tatvan State Hospital; ∥Department of Neurology, Bitlis State Hospital, Bitlis; ¶Department of Rheumatology, Ankara Numune Education and Research Hospital,Ankara; and **Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy.
  1. Received December 9, 2010, and in revised form February 11, 2011.
  2. Accepted for publication February 24, 2011.
  3. Reprints: Cumali Efe, MD, Department of Gastroenterology, Hacettepe University School of Medicine, 06100 Sihhiye, Ankara, Turkey. E-mail: drcumi21{at}hotmail.com.
  4. There is no conflict of interest to declare.

Abstract

Atherosclerosis is a dynamic process in the human body. Many studies have evaluated atherosclerosis and its relationship with other systems in the body. Our perception of its pathogenesis is evolving with the introduction of new players in the game. It is no longer possible to consider the atherosclerosis as an independent process, unaffected by the liver and its function. Although several tasks performed by the liver, such as lipid metabolism, have been implicated in the pathogenesis of atherosclerosis, the role of other disorders of the liver (autoimmune diseases, viral hepatitis, and cirrhosis) are not fully understood. In this review, the most commonly encountered inflammatory liver diseases and their effects on atherosclerosis are discussed.

Key Words
  • hepatitis B
  • hepatitis C
  • hepatitis A
  • inflammation
  • fatty liver
  • atherosclerosis

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Key Words

Atherosclerosis-related diseases remain an important health issue in the modern world despite research aimed at understanding the underlying pathogenesis. On the other hand, chronic hepatitis is defined as the presence of liver inflammation, characterized by several clinical, histological, and laboratory findings, lasting more than 6 months. It may occur as a result of several etiologies, most commonly chronic viral hepatitis, autoimmune liver diseases, and nonalcoholic fatty liver disease (NAFLD). Regardless of cause, cirrhosis eventually develops if the underlying condition is left untreated.

The liver and its metabolic functions are widely believed to be a part of the atherosclerotic process. Although some tasks performed by the liver, such as lipid metabolism, have been well studied in terms of pathogenesis of atherosclerosis, the association between atherosclerosis and other disorders of the liver, including autoimmune diseases, viral hepatitis, and cirrhosis, is not fully understood. In this review, the most commonly encountered inflammatory liver diseases and their relationship with atherosclerosis are discussed, with particular reference to possible interactions between liver diseases, cirrhosis, and atherosclerosis.

HEPATITIS VIRUSES

Hepatitis A Virus

Hepatitis A virus (HAV), an RNA virus that spreads via the fecal-oral route, remains a public health problem despite the fact that an effective vaccine has been introduced into routine clinical practice. Hepatitis A virus is known to result in acute infection, although, in some cases, viremia may persist for up to 6 months.1-3Although the virus does not result in a chronic infection or inflammation of the liver, some studies, summarized in Table 1, have reported on a casual link between HAV and atherosclerosis, whose chronicity is well established.

TABLE 1.

Studies Evaluating the Risk of Atherosclerosis With HAV

Zhu et al.4demonstrated an association between HAV, elevated C-reactive protein (CRP), and coronary atherosclerosis. Despite the common belief that HAV does not cause chronic persistent infection in the human body, some authors suggest that HAV may in fact lead to a chronic persistent infection, evidenced by elevated CRP levels and, in turn, atherosclerosis. Zhu et al. brought forward 2 explanations for this prolonged effect of HAV. They postulated that ongoing inflammation due to a recurring, clinically undetectable HAV infection sets the stage for the progression of atherosclerosis. In other words, they believed that elevated levels of CRP and antibodies against HAV serve as markers for the continuum of the inflammation. Another suggestion was that HAV and blood vessels share antigenic similarities, making the vessel wall a target for the immune system (Fig. 1). Initial contact with the virus during infancy may facilitate the development of cross-reacting antibodies with host peptides.4

FIGURE 1.

Potential mechanisms by which viral hepatitis and NAFLDs may promote atherosclerosis. The increased inflammatory state creates an environment for increased oxidative stress, which is further enhanced by the presence of insulin resistance and atherogenic dyslipidemia. This leads to the release of several cytokines, such as CRP, interleukin 6, fibrinogen, and plasminogen activator inhibitor 1. Measurement of these cytokines in the plasma may help to promote effective strategies of cardiovascular prevention. This is of particular importance for HAV infection and NAFLDs. IL-6 indicates interleukin-6; PAI-1, plasminogen activator inhibitor 1.

In contrast, Ongey et al.5could not demonstrate an increased risk for cardiovascular diseases (CVDs) in association with HAV while also reporting on no adverse effects on the lipid profiles of infected patients. Based on the results of an interesting study by Burnett et al.,6it was suggested that the presence of antibodies against HAV, including as a result of vaccination, could make affected patients susceptible to atherosclerosis. Subsequently, the authors set up a murine model to test their hypothesis and found no association between vaccination and an added atherosclerosis risk. Despite the known limitations of animal studies, the authors concluded that simple seropositivity alone was not enough to trigger the atherosclerotic process but that a true infection is required. They also hypothesized that cross reactivity between human proteins (injured vessel) and virus epitopes are required to activate the autoimmune response.

On the other hand, Auer et al.7failed to show an association between HAV seropositivity and coronary atherosclerosis. They emphasized that a single pathogen alone was insufficient to create an atherosclerotic environment and that the involvement of multiple pathogens offered a more logical explanation for infection-induced atherosclerosis. As such, the term pathogen burden has been coined to describe the contribution of numerous pathogens to endothelial dysfunction. In a study by Szklo et al.,8designed to investigate a possible role of "pathogen burden" on atherosclerosis, an association could not be established. The authors also could not ascertain a link between any individual pathogen and atherosclerosis. Despite the conflicting results of the above-mentioned studies, most of the evidence points to a strong association between markers of infection and subclinical atherosclerosis. In a recent study, pathogen burden was found to be independently associated with the future occurrence of cerebrovascular and cardiovascular events in patients with asymptomatic baseline carotid lesions.9

Hepatitis B Virus

The exact role of the chronic hepatitis B virus (HBV) infection, an important public health problem, in the atherosclerotic process remains a matter for debate, besides being a very exciting area of research. Most of the studies in the current literature that have investigated a causal relation between HBV seropositivity and atherosclerosis are cross-sectional, involving a small patient population. The only large-scale prospective study was from Taiwan.10In many of the published studies, only a causal relationship between HBsAg status and some parameters related to atherosclerosis, such as carotid atherosclerosis, coronary flow reserve (CFR), coronary atherosclerosis, and duplex velocity waves, has been investigated. However, none of these reports has offered conclusive evidence supporting a direct link between HBV seropositivity and atherosclerosis. Some authors have suggested that the presence of HBV infection may be a protective factor for atherosclerosis because of low cholesterol and Lp(a) levels. In support, none of the studies reported on elevated CRP levels in association with HBV seropositivity.

Hepatotropic viruses, such as HAV, HBV, and hepatitis C virus (HCV), and their positive or negative association with atherosclerosis have offered an intriguing new area of research that has been exploited, albeit with conflicting results. In a follow-up study from Taiwan, Wang et al.11suggested that HBsAg seropositivity was not a significant predictor for atherosclerosis-related cardiovascular deaths after adjusting for confounding factors. The value of this study lies in the fact that it was designed as a prospective analysis with a large patient population, where mortality due to cardiac events possibly related to HBV was investigated. In another study, Yang et al.10found no association between carotid atherosclerosis and HBV seropositivity, a result consistent with the findings by Wang et al. In yet another cohort, Tong et al.12evaluated the association between coronary atherosclerosis and HBV. Interestingly, although they could not establish such an association, they discovered a negative correlation between CRP levels and HBV serological status.

Suggested mechanisms for HBV-related atherosclerosis are as follows: direct vascular damage by the virus, vasculitic effect as an extrahepatic manifestation, accelerated oxidative damage induced by HBV and immunological response driven by the virus (Fig. 1). Notably, Ishizaka et al.13observed in their study that HBV carriers were prone to carotid atherosclerosis. Studies evaluating the relationship between HBV and atherosclerosis have been summarized in Table 2.

TABLE 2.

Studies Evaluating the Risk of Atherosclerosis With HBV

It would seem that the evidence presented by these studies is inconclusive, and further randomized controlled prospective trials are needed to make a clear-cut judgment on the matter.

Hepatitis C Virus

Hepatitis C virus infects nearly 3% of the world population, and infection follows a chronic course in most cases.14-16In recent years, the potential association between chronic HCV infection and the metabolic syndrome has gained interest, particularly for research on the association between chronic HCV and atherosclerosis.

Alyan et al.17evaluated the role of HCV status as an aggravating factor for atherosclerosis in patients with proven coronary artery disease (CAD), using the Reardon severity score system. This score was first introduced by Reardon et al.18to describe the degree of narrowing of the coronary microcirculation based on angiographic findings. Authors reported HCV seropositivity to be a potent risk factor for atherosclerosis, with the presence of elevated fibrinogen and CRP levels being associated with a more severe clinical presentation and extensive multivessel involvement, compared with the healthy controls.

Boddi et al.19were the first to detect the presence of HCV, particularly of genotype 2, within plaque tissue, suggesting that the virus may play a pivotal role during the development of atherosclerosis. They also reported on a close association of the virus with the metabolic syndrome and insulin resistance, the clinical importance of which remains unknown (see figure). In an interesting report, it was demonstrated that HCV could infect peripheral blood mononuclear cells and liver without evidence of the infection in the serum.20These findings may be explained by the presence of an occult HCV infection, and carotid plaques may be among the tissues in which the virus is lodged and remains hidden.

In a conflicting report, Bilora et al.21reported on a protective role of chronic viral hepatitis (B and C) on atherogenic plaque formation in the carotid, abdominal, and femoral regions. In this 5-year follow-up study, they observed a protective effect of HCV seropositivity and chronic HCV infection against carotid and femoral atherosclerosis. In addition to serological evidence of HCV, the authors also evaluated liver histological findings. In another study, Ishizaka et al.22pointed out that chronic HCV infection may accelerate the atherosclerotic process in the carotid artery via several proposed mechanisms. In 2002, they had evaluated the connection between HCV seropositivity and carotid intima-media thickness (CIMT). After 1 year of follow-up, the investigators switched to detection of HCV core protein as a screening method for chronic HCV infection, which they believed to be a more reliable marker of ongoing infection. They discovered a positive correlation between core-protein positivity and increased CIMT. They suggested that rather than anti-HCV positivity, which was used in previous studies, core protein positivity, as a better indicator of ongoing infection, was more strongly associated with carotid plaque formation which is of key importance in the development of atherosclerosis. On a different note, Arcari et al.23could not establish an association between HCV and acute myocardial infarction (MI) in a study on young male subjects from the US military.

In a Japanese study, Tomiyama et al.24evaluated arterial stiffness in 7514 patients, 87 of which were seropositive for HCV and 76 for HBV, by measuring ankle-brachial pulse wave velocity with a specially designed device. A comparison of groups revealed a positive correlation between HCV seropositivity and arterial stiffness indicating atherosclerosis but not so with HBV. However, in a conflicting report by Volzke et al.,25neither of HCV or HBV was found to be associated with carotid atherosclerosis and the clinical occurrence of CVD, such as stroke and MI.

In 2007, Targher et al.26investigated a tentative role of NAFLD, chronic HBV, and chronic HCV infection in the development of early atherosclerosis. In this intriguing Italian study, all 3 diseases were found to be responsible for the development of carotid atherosclerosis, in comparison to healthy controls. Studies evaluating the relationship between HCV infection and atherosclerosis have been summarized in Table 3.

TABLE 3.

Studies Evaluating the Risk of Atherosclerosis With HCV

Other Viruses

Among the other viruses, herpes viruses and cytomegalovirus are the most studied with confirmed associations with the development and progression of atherosclerosis.27,28So far, no study has directly evaluated the potential effects of hepatitis E virus and hepatitis G virus infections on atherosclerosis. On the other hand, hepatitis D virus infection cannot be considered as a separate entity because by nature it depends primarily on HBV to invade a host. None of the current studies on HBV positive patients have included those coinfected or superinfected with HDV.

Common Limitations of Studies on Hepatitis Viruses

Most of the aforementioned studies are cross-sectional in nature and include small cohorts, without taking into consideration ethnic differences. Furthermore, most studies have focused on the role of single pathogens in the pathogenesis of atherosclerosis, which may not truly reflect a real causal relation. Studies should be undertaken in terms of pathogen burden (all possible viruses and bacteria) rather than taking into consideration single pathogens.

Furthermore, serological status does not necessarily indicate a direct role of a virus in the atherosclerotic process, especially in the absence of histopathological examination of the liver. Most studies have not included liver biopsy as part of the methodology. The serological profile of HCV or HBV may indicate active replication, which may not reflect the extent of damage to the liver, if at all. For this reason, it is prudent to consider the direct and indirect effects of a virus separately when undertaking a study on the subject matter. As an example, investigation of indirect effects of liver on the atherosclerotic process, such as a favorable lipid profile and/or decreased Lp(a), warrant confirmation with a liver biopsy. However, even in the presence of a liver biopsy, the effect of occult HBV and HCV on the atherosclerotic process may not be determined accurately.

Even if we accept the presence of a causal relationship between chronic hepatitis and atherosclerosis implied by these studies, some benefit would be expected from appropriate therapy. As a next step, future studies should focus on the effects of treatment on the atherosclerotic process rather than look for an association with liver disease. Moreover, any such study should not include patients with established cirrhosis because the cirrhotic liver has many characteristics differentiating it from the noncirrhotic liver, such as low platelet count, coagulopathy, decreased cholesterol and Lp(a) level, and decreased CRP level, all of which may have significant effects on study results.

NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease is a group of metabolic disorders that affects multiple organ systems in the body. Dealing with it as a separate, isolated entity is not a logical approach to understanding the disease. Its close relationship with the metabolic syndrome has been well studied till now; however, it remains unknown whether it is a consequence or a cause of the metabolic syndrome.

The prevalence of NAFLD is estimated as 15% to 30% in the general population, and given its close association with the metabolic syndrome, several cardiovascular risk factors, such as hypertension, dyslipidemia, obesity, and type-2 diabetes, frequently occur simultaneously.29Traditionally, NAFLD comprises a wide spectrum of clinical disorders, from simple steatosis and nonalcoholic steatohepatitis (NASH) to end-stage liver disease. Noncirrhotic, nonalcoholic fatty liver is classified as simple steatosis and NASH. The diagnosis is based on appropriate clinical history, exclusion of other liver diseases, imaging modalities such as ultrasonography and magnetic resonance imaging, and liver biopsy. Liver biopsy is the only definitive way to differentiate between simple steatosis, NASH, and cirrhosis. Simple steatosis is a much more benign condition compared with NASH in that it carries a lower risk of progression to end-stage liver failure. As a result, different projections could be expected from these 2 entities in clinical practice.

Nonalcoholic fatty liver disease and its contribution to increased CVD risk have been extensively studied. Targher et al.30assessed 2000 type 2 diabetes mellitus patients with respect to the development of disorders associated with atherosclerosis during a follow-up period of 6.5 years. A total of 384 patients experienced CVD events, such as MI or stroke. This association was found to be independent from the classical risk factors in diabetic subjects. In another study, the same group looked into the prevalence of NAFLD in patients with type 1 diabetes, where they attempted to establish the frequency of CVD in the presence of NAFLD. After correction for age and sex, the prevalence of CVD was found to be higher in patients with NAFLD than in those without (coronary artery disease, 10.8%; cerebrovascular disease, 37.3%; and peripheral vascular disease, 24.5%).31

Markers of subclinical atherosclerosis, such as CIMT and brachial artery flow-mediated dilatation (BA-FMD), have been used as measures of endothelial dysfunction in patients with NAFLD. In a study evaluating CIMT in patients with biopsy-proven NAFLD, Targher and Arcaro29and Targher et al.32demonstrated higher measurements when compared with healthy controls. Moreover, they established histological severity to be an independent risk factor for CIMT. In a meta-analysis by Sookoian and Pirola33on 3947 patients, NAFLD was found to be a risk factor for increased CIMT.

Another test used to evaluate endothelial dysfunction is BA-FMD. Villanova et al.34published a study on the effect of NAFLD on BA-FMD. In this study, nondiabetic NAFLD patients showed an abnormal pattern compared with the healthy controls. This abnormality was well correlated with histological severity.29

On the other hand, in a study on patients with biopsy-proven NASH, Yilmaz et al.35investigated changes in CFR by using an echocardiographic technique to examine coronary microcirculation. They reported on a negative correlation between liver fibrosis and CFR, translating with more impairment in CFR as liver fibrosis progresses.

There is no doubt that NASH is associated with a more severe inflammatory milieu. In this regard, some studies have shown that patients with NASH are more prone to developing atherosclerosis compared with those with simple steatosis.36-39The increased inflammatory state associated with fatty change in the liver creates an environment for increased oxidative stress that, in turn, leads to release of several cytokines such as CRP, interleukin 6, and plasminogen activator inhibitor 129,39-45(Fig. 1). Decreased adiponectin levels also are a contributing factor for the development of atherosclerosis in this inflammatory milieu.29,46-49

In a study by Yun et al.,50elevations in ALT levels, as an indirect marker of inflammation for NASH, were demonstrated in association with subclinical atherosclerosis. They recruited 37,085 patients with a median follow-up of 5 years during which time 407 deaths occurred. Ninety deaths were attributed to diabetes or CVD. As a result, they concluded that increased ALT levels were associated with higher mortality due to CVD or diabetes. In a separate study, however, increased ALT levels were found to be irrelevant with regard to the development of CVD.51

Recently published data support the presence of an increased risk of CVD in patients with elevated GGT levels; however, this risk is more pronounced in young subjects compared with older patients. Nevertheless, as a prognostic marker in this setting, the contribution of GGT is weak.

To date, several abnormalities of lipid metabolism have been described in association with NAFLD. Charlton et al.52reported that Apo B 100 synthesis is a triggering event for the development of hepatic steatosis while also contributing to insulin resistance which is the hallmark of the metabolic syndrome. Others have suggested a possible role of postprandial lipoproteins, which have been shown to be more vulnerable to oxidation during the postprandial period, in the development of atherosclerosis. A strong correlation between this phenomenon and severity of liver histology has been demonstrated in patients with NAFLD compared with healthy subjects.29,53,54In another study, postprandial lipemia was found to promote atherosclerosis in aortic endothelium via the induction of ICAM-1 expression.54,55Similarly, Alkhouri et al.56reported on a positive correlation between an atherogenic lipid profile (increased triglyceride/high-density lipoprotein [HDL], low-density lipoprotein [LDL]/HDL, and cholesterol/HDL) and NASH. They established that after exclusion of other confounding factors, NASH created a propensity for the development of an atherogenic lipid profile.

On another note, some authors believe that the level of insulin resistance is in proportion to the degree of fatty change in the liver,29,52-54,57,58which may be another contributing factor in the development atherosclerosis.

There is an ongoing debate on whether NAFLD is a consequence or cause of CVD. Some specific NAFLD groups, with additional risk factors, seem to be prone to developing CVD. In this group, early diagnostic and therapeutic interventions might be a logical approach. Future studies could bring a fresh perspective regarding the role of NAFLD on atherosclerotic cardiovascular events.

CHRONIC CHOLESTATIC LIVER DISEASES

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disorder of unknown etiology that mainly affects middle-aged women. It generally follows a progressive course and ultimately necessitates liver transplantation.59-62Traditionally, PBC is associated with hypercholesterolemia and changes in lipoprotein. However, the role of these changes in the development of atherosclerosis in PBC has not been very easy to establish, and our growing knowledge on this issue has exposed the complexity of the problem. It is common knowledge that hypercholesterolemia is a strong risk factor for atherosclerosis; however, data on hypercholesterolemia associated with PBC regarding cardiovascular risk is inconclusive. Furthermore, patients with PBC are at varying risk for the development of atherosclerosis depending on the stage of the disease, which adds some degree of difficulty.60,63In the initial and middle phases, slightly increased very-low-density lipoprotein, LDL, and strikingly elevated HDL concentrations are notable in comparison to levels during the late/end stage phase of the disease.60,64-66Triglyceride levels are decreased in PBC, and the decrease continues as the disease progresses because of decreased hepatic lipase action.67

In PBC, cholesterol particles harbor a great amount of LP-x, which is known to be protective against atherosclerosis. This protective role could be explained by the inhibitory effect imposed by Lp-x particles on oxidation of LDL particles.60,68In fact, some authors believe that the LP-x acts in a fashion similar to HDL, which is known to "sweep" LDL particles from peripheral tissue.69

In a limited prospective study from 1992, Crippin et al.66evaluated the risk of atherosclerosis in 312 patients with PBC. During a median follow-up of 7.4 years, they discovered that the rate of atherosclerosis-related deaths did not differ in patients with or without PBC (n = 128). Nevertheless, this study is not without its limitations. The cause of death in this study was based on information recorded on death certificates. This may not have reflected the true cause of death because the reason recorded on the certificates is usually left to the discretion of the attending physicians, resulting in some degree of subjectivity. Another drawback of this study is the limited use of autopsies, which may translate to subclinical atherosclerosis being overlooked.

In another study on 400 PBC patients, Longo et al.70could not establish an added risk of CVD associated with hypercholesterolemia when compared with healthy controls. Van Dam and Gips71performed a retrospective analysis on 596 PBC patients who presented between 1979 and 1992. In this study, the increase in cardiovascular mortality in PBC patients did not reach statistical significance. It should be noted that studies evaluating the association of PBC and atherosclerosis have mainly focused on the link between hypercholesterolemia and cardiovascular mortality. However, it is worth noting that PBC is an autoimmune disorder of the liver and that it may be associated with impaired liver function, besides cholesterol metabolism, which also may play a role in the development of atherosclerosis. A limited number of studies did not demonstrate a positive correlation between PBC and atherosclerosis.

Some authors have suggested a protective role for PBC against the development of atherosclerosis because of the altered lipid profile. Another group of investigators emphasized that elevated serum bilirubin, with its antioxidant effect, might be a protective factor for atherosclerosis,72,73as has been demonstrated by Dudnik et al.74In their study, they revealed that elevated serum bilirubin levels worked to decrease oxidative stress.

There remains a need for large scale, randomized prospective studies with long-term follow-up periods, evaluating multiple factors to fully establish the presence or absence of a real association.

Interestingly, a search of the English literature on the association between atherosclerosis and other autoimmune diseases or primary sclerosing cholangitis did not reveal any studies of note.

CIRRHOSIS

Cirrhosis is a term that describes various pathological changes involving the liver and often is used as a clinical description indicating the onset of end stage liver disease, occurring as a result of a wide array of etiological factors. Several pathophysiological changes that could affect the atherosclerotic process take place in the cirrhotic liver. Decreased production of cholesterol by the liver, peripheral vasodilatation and decreased systemic blood pressure due to increased nitric oxide production, a low platelet count, and impaired hemostasis are believed to be responsible for the low prevalence of atherosclerosis in patients with cirrhosis. Some authors also have proposed that the hyperestrogenic state seen in cirrhosis conveys a protective effect against atherosclerosis, as has been described in premenopausal female subjects75,76(Table 4).

TABLE 4.

Suggested Mechanisms for the Protective Effects of Cirrhosis on Atherosclerosis 75,76

Based on autopsy findings, a negative correlation between cirrhosis and atherosclerosis was proposed by some authors.76,77In an autopsy series, Vanecek76investigated the prevalence of atherosclerosis in 507 cirrhotic subjects (317 male and 190 female subjects). They discovered that calcifications of the aorta and coronary arteries were more common in cirrhotics compared with noncirrhotics, particularly in male subjects. However, they also reported on low rates of recent MI and myocardial damage in both sexes. In a conflicting study, Marchesini et al.78reported on a low prevalence of atherosclerosis in cirrhotic subjects, despite the concomitant presence of type 2 diabetes. Here, the authors evaluated several parameters, such as ankle brachial pressure, arterial hypertension, and CAD and concluded that cirrhosis was not a risk factor for atherosclerosis. They suggested that cirrhosis might even have a protective role against diabetic complications that are known to significantly decrease the life span of patients with diabetes mellitus, compared with noncirrhotic controls. In another study, in which Tamura et al.79used CIMT as an indicator of atherosclerosis, patients were examined in 3 groups to determine the effect of cirrhosis on atherosclerosis. They postulated that decreased fibrinogen levels and a low platelet count may have a protective effect in cirrhotic patients with diabetes.

Kadayifci et al.80attempted to establish potential differences in the development of atherosclerosis in patients with cirrhosis because of NAFLD or other etiologies. The investigators observed that the protective effects of cirrhosis on atherosclerosis did not manifest in patients with NAFLD and that the proatherosclerotic factors such as insulin resistance, metabolic syndrome, and obesity remained paramount.

Overall, evidence points toward a protective effect of cirrhosis on atherosclerosis. However, the underlying proatherosclerotic mechanisms associated with NAFLD overcome this protective effect to accelerate the atherosclerotic process. This highlights the importance of determining the etiology in patients with so called cryptogenic cirrhosis. As with the other inflammatory liver diseases, full comprehension of the mechanisms requires the completion of large scale, randomized, controlled studies with a long-term follow-up.

CONCLUSIONS

Atherosclerosis is a complex process with multifaceted mechanisms. It is well known that inflammation represents a crucial step for atherosclerosis. It would seem that liver inflammation plays a role in the atherosclerotic process. However, as an organ with multiple functions, inflammation of the liver alone is not the sole contributor for atherosclerosis. Results of present studies evaluating the atherosclerotic potential of hepatitis viruses are inconclusive with regard to a possible role of these microorganisms in the atherosclerotic process.

Hepatitis A virus does not result in chronic hepatitis, and the indirect effects of HAV have only been suggested to play a role in atherosclerosis, in contrast to HBV and HCV which have been directly implicated. Molecular similarities with the vessel wall and subclinical chronic infection with resultant chronic inflammation are proposed mechanisms for HAV. Chronic HBV infection, on the other hand, exerts its action both directly and indirectly while promoting the development and progression of atherosclerosis. Direct vascular damage by the virus, indirect immunological activation, and extrahepatic involvement, such as vasculitis, are the main mechanisms described in the pathogenesis of atherosclerosis. Studies on the effects of HCV and the underlying pathology associated with chronic HCV infection have reported on subtle differences from HBV. Some have demonstrated the presence of HCV viral core proteins in atherosclerotic plaques, whereas others have described a possible association with the metabolic syndrome, particularly with HCV genotype 2. A combination of both of these proposed mechanisms is widely believed to contribute to the development of atherosclerosis. Although isolation of the virus from atherosclerotic plaques is an important finding, its clinical significance remains elusive, especially in the setting of an occult hepatitis C infection. The lack of liver biopsies in most studies on viral hepatitis virus limits their value. Future studies should take into account occult HBV and HCV infections, and the effect of antiviral treatment on the atherosclerotic process is a potential target for further research.

The altered lipid metabolism in primary biliary cirrhosis is widely believed to be a risk factor for atherosclerosis. However, there is a dire need for large scale controlled trials with long-term follow-up to elucidate this association.

The strongest body of evidence, when compared with other liver diseases, supports the association between NAFLD and atherosclerosis. Nonalcoholic steatohepatitis, which reflects a more severe inflammatory state of the liver, potentially poses a greater risk than simple steatosis. Whether NAFLD is a result or a cause of atherosclerosis remains unknown, and histological progression or regression of NAFLD during the atherosclerotic process needs to be clarified by the future studies. Currently, the association of NAFLD with an increased risk of CVD is of particular importance, especially in some groups with additional risk factors. Further research directly evaluating the relationship between primary sclerosing cholangitis or autoimmune hepatitis and atherosclerosis needs to be undertaken.

References