clearly associated to a rapid induction of a broad-rangeneutralizing antibodies in the early phase of infection,while inability to eradicate the virus was characterizedby low neutralizing antibody titers at the same time points[4]. Collectively, these data indicate that production of abroad-range neutralizing humoral response can be crucialfor viral clearance, in line with findings in HIV infection,in which neutralizing antibodies act in concert with cell-mediated responses for the control of infection [5].

Several well-characterized human monoclonal anti-bodies (mAb) endowed with broad-range neutralizingactivity at very low concentrations and recognizing theAR3 epitope have been described and are available today[6,7]. Each of these molecules is a potential new tool forprevention and treatment of HCV infection. Indeed, pro-phylaxis with a single mAb or with a mixture of synergicmAbs, can protect from infection; however, this shouldbe tested in the experimental chimpanzee model ofHCV infection. Moreover definition of conserved B-cellepitopes able to elicit protective immunity can be a keyelement for the design of more effective vaccines.

Conserved regions, such as the one identified by Lawet al., are particularly attractive as their mutation can bedetrimental to the HCV life cycle. Passive administra-tion of human monoclonal antibodies directed againstthese conserved epitopes would force the virus to mutatein functionally important regions, and this may repre-sent a novel therapeutic approach in those patientswho did not respond to current treatments. Antiviralcompounds targeting crucial viral proteins have beendemonstrated to be effective in inducing a modificationof the viral replication capacity as well as the pathogenicpotential of rapidly evolving RNA viruses [8]. HumanmAbs directed against conserved HCV epitopes withbroad-range neutralization activity are promising

antiviral compounds that, through their unique mecha-nism of action, could be useful in preventing and treat-ing HCV infection.

References

[1] Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z,et al. Broadly neutralizing antibodies protect against hepatitis Cvirus quasispecies challenge. Nat Med 2008;14:25–27.

[2] Burioni R, Matsuura Y, Mancini N, Tani H, Miyamura T, VaraldoPE, et al. Diverging effects of human recombinant anti-hepatitis Cvirus (HCV) antibody fragments derived from a single patient onthe infectivity of a vesicular stomatitis virus/HCV pseudotype. JVirol 2002;76:11775–11779.

[3] Lavillette D, Morice Y, Germanidis G, Donot P, Soulier A,Pagkalos E, et al. Human serum facilitates hepatitis C virusinfection, and neutralizing responses inversely correlate with viralreplication kinetics at the acute phase of hepatitis C virus infection.J Virol 2005;79:6023–6034.

[4] Pestka JM, Zeisel MB, Blaser E, Schurmann P, Bartosch B, CossetFL, et al. Rapid induction of virus-neutralizing antibodies and viralclearance in a single-source outbreak of hepatitis C. Proc NatlAcad Sci USA 2007;104:6025–6030.

[5] Igarashi T, Brown C, Azadegan A, Haigwood N, Dimitrov D,Martin MA, et al. Human immunodeficiency virus type 1 neutral-izing antibodies accelerate clearance of cell-free virions from bloodplasma. Nat Med 1999;5:211–216.

[6] Keck ZY, Machida K, Lai MM, Ball JK, Patel AH, Foung SK.Therapeutic control of hepatitis C virus: the role of neutralizingmonoclonal antibodies. Curr Top Microbiol Immunol 2008;317:1–38.

[7] Perotti M, Mancini N, Diotti RA, Tarr AW, Ball JK, Owsianka A,et al. Identification of a broadly cross-reacting and neutralizinghuman monoclonal antibody directed against the hepatitis C virusE2 protein. J Virol 2008;82:1047–1052.

[8] Clementi M, Burioni R. Is reduction of viral fitness a valid antiviralapproach? Drug Discov Today: Ther Strategies 2008. doi:10.1016/j.ddstr.2007.12.001.

doi:10.1016/j.jhep.2008.05.008

Liver and heart: A new link? q

Stefano Bellentani1,*, Giorgio Bedogni1,2, Claudio Tiribelli2

1Centro Studi Nutrizione e Fegato, Ospedale ‘‘Ramazzini’’ Carpi – Azienda USL di Modena, Via G. Molinari, 2 Carpi 42100, Italy2CSF – Bassovizza and University of Trieste, Italy

Alanine aminotransferase predicts coronary heart

disease events: a 10-year follow-up of the Hoorn Study.

Schindhelm RK, Dekker JM, Nijpels G, Bouter LM,

Stehouwer CD, Heine RJ, Diamant M.

Alanine aminotransferase (ALT) is a marker of non-

alcoholic fatty liver disease (NAFLD) and predicts inci-

dent type 2 diabetes mellitus (DM2). Recently, ALT

was shown to be also associated with endothelial

dysfunction and carotid atherosclerosis. We studied the

predictive value of ALT for all-cause mortality, incident

cardiovascular disease (CVD) and coronary heart disease

(CHD) events in a population-based cohort of Caucasianmen and women aged 50–75 years, at baseline. The

q The authors declare that they do not have anything to discloseregarding funding from industries or conflict of interest with respect tothis manuscript.

* Corresponding author. Tel.: +39 059 659370; fax: +39 059 851762.E-mail addresses: stefano.bellentani@unimore.it, s.bellentani@

ausl.mo.it (S. Bellentani).

300 Journal Clubs / Journal of Hepatology 49 (2008) 299–302

10-year risk of all-cause mortality, fatal and non-fatal

CVD and CHD events in relation to ALT was assessed

in 1439 subjects participating in the Hoorn Study, using

Cox survival analysis. Subjects with prevalent CVD/CHD and missing data were excluded. As compared with

the first tertile, the age- and sex-adjusted hazard ratios(95% confidence intervals) for all-cause mortality, CVD

events and CHD events were 1.30 (0.92–1.83), 1.40

(1.09–1.81) and 2.04 (1.35–3.10), respectively, for subjects

in the upper tertile of ALT. After adjustment for

components of the metabolic syndrome and traditional

risk factors, the association of ALT and CHD events

remained significant for subjects in the third relative to

those in the first tertile, with a hazard ratio of 1.88(1.21–2.92) and 1.75 (1.12–2.73), respectively. In

conclusion, the predictive value of ALT for coronary

events, seems independent of traditional risk factors and

the features of the metabolic syndrome in a population-

based cohort. Further studies should confirm these findings

and elucidate the pathophysiological mechanisms.

[Abstract reproduced by permission of Atherosclerosis

2007;191:391–396]

The relationship between liver and heart diseases hasbeen historically a matter of debate. Cardiac hyperdy-namic abnormalities, characterized by increased baselinecardiac output and mean arterial pressure, were firstreported in 1953 by Kowalski & Abelmann in patientswith cirrhosis [1]. Today, the complex hemodynamicalterations present in cirrhotic patients are classified as‘‘cirrhotic cardiomyopathy”, and are recognized to playa role in the pathogenesis of the hepatorenal syndromeand in the mortality associated with TIPS insertion orliver transplantation. However, both old and modernclinicians would certainly agree that when the liver isdamaged as in cirrhosis, the principal clinical problemis the liver and not the heart.

With the appearance on the clinical scenario of non-alcoholic fatty liver disease (NAFLD), and with therapid recognition that NAFLD is the commonest hepa-tic disorder in the developed world affecting up to athird of individuals and the increasing number of heartdisease, the relationship between liver and the hearthas been revisited. It is becoming increasingly evidentthat the so-called ‘‘metabolic syndrome” (MS) repre-sents the main link between liver and heart diseases[2]. Subjects with MS are in fact considered at risk ofcardiovascular and coronary heart disease, althoughthe clinical usefulness of this syndrome is still debated[3,4].

Recent studies have stressed the importance of fattyliver as an independent predictor of some cardiovascularoutcomes [2,5]. Other studies have shown that subjects

with abnormal liver enzymes, mainly ALT, are at riskof developing hypertension and diabetes. In addition,NAFLD has been associated with surrogate cardiovas-cular outcomes such as endothelial dysfunction, abnor-mal vascular reactivity, increased carotid intimalthickness and the number of carotid plaques [5,6].Recently, in a prospective study, Ekstedt and colleagueshave shown that the 14-year risk of cardiovascularmortality is doubled in tertiary care patients withbiopsy-proven NAFLD as compared to a referencepopulation [7].

Cardiac lipotoxicity is a well-described phenomenonassociated with insulin resistance, and is generally attrib-uted to an excess production of free fatty acids [8].Perseghin and colleagues have recently shown that indi-viduals with an increased amount of fat in the liver havealso an increased amount of epicardial fat [9]. Despitealterations in cardiac metabolism detected by phospho-rous magnetic resonance spectroscopy, these subjectshad a normal morphology and function of the heart.

In the general population of the Hoorn Study,Schindhelm and colleagues reported that elevated serumALT activity significantly increased the 10-year risk ofcoronary hearth disease, even after adjustment for alco-hol intake and for the component of MS. They con-cluded that in the general population, ALT is apredictor of 10-year cardiovascular mortality indepen-dently of traditional cardiovascular risk factors, suchas systolic blood pressure, HbA1c, LDL-cholesteroland BMI [10]. As acknowledged by the Authors, thestudy has several limitations: (1) a highly selected popu-lation (Caucasians aged 50–75 years); (2) the lack ofinformation on non-fatal disease; (3) the use of ALTas a surrogate marker of NAFLD in place of more reli-able imaging or histological procedures; and (4) the lackof exclusion of ALT elevations due to hepatotropicviruses and drugs. Despite these shortcomings the mes-sage of the study is clearly important. An additionalproblem to be considered is that not all the patients withfatty liver do show increased ALT level as recently dem-onstrated in the general population of the DionysosStudy where 50% of subjects with steatosis detected byultrasonography had normal levels of ALT [11]. TakingALT as the only surrogate marker of NAFLD, insteadof performing hepatic ultrasound to find out if steatosiswas present, probably underestimates the predictivevalue of ALT, questioning the validity of the message.

Collectively, the paper by Schindhelm and colleagues[10] challenges the assumption that ALT is only a mar-ker of liver disease, and strongly suggests that elevationof ALT and NAFLD are associated with increased riskof cardiovascular disease, and are independent predic-tors of cardiovascular mortality. Further studies areneeded to confirm these findings and to evaluate the pos-sibility that NAFLD may or may not be an early marker(or mediator) of atherosclerosis, and possibly unravel

Journal Clubs / Journal of Hepatology 49 (2008) 299–302 301

what is the trigger for lipotoxicity in the liver or in theheart. In the meantime, there is a clear take-home mes-sage for the practising physician: perform an evaluationof common cardiovascular risk factors in patients withelevated ALT or NALFD [6].

References

[1] Kowalski HJ, Abelmann WH. The cardiac output at rest inLaennec’s cirrhosis. J Clin Invest 1953;32:1025–1033.

[2] Dekker JM, Girman C, Rhodes T, Nijpels G, Stehouwer CD,Bouter LM, et al. Metabolic syndrome and 10-year cardiovasculardisease risk in the Hoorn Study. Circulation 2005;12:666–673.

[3] Gale EA. Should we dump the metabolic syndrome? Yes. BMJ2008;336:640.

[4] Alberti KG, Zimmet PZ. Should we dump the metabolicsyndrome? No. BMJ 2008;336:641.

[5] Targher G. Non-alcoholic fatty liver disease, the metabolicsyndrome and the risk of cardiovascular disease: the plot thickens.Diabet Med 2007;24:1–6.

[6] Loria P, Lonardo A, Bellentani S, Day CP, Marchesini G, CarulliN. Non-alcoholic fatty liver disease (NAFLD) and cardiovasculardisease: an open question. Nutr Metab Cardiovasc Dis2007;17:684–698.

[7] Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M,Bodemar G, et al. Long-term follow-up of patients with NAFLDand elevated liver enzymes. Hepatology 2006;44:865–873.

[8] Unger RH. Lipotoxic diseases. Annu Rev Med 2002;53:319–336.[9] Perseghin G, Lattuada G, De Cobelli F, Esposito A, Belloni E,

Ntali G, et al. Increased mediastinal fat and impaired leftventricular energy metabolism in young men with newly foundfatty liver. Hepatology 2008;47:51–58.

[10] Schindhelm RK, Dekker JM, Nijpels G, Stehouwer CD, BouterLM, Heine RJ, et al. Alanine aminotransferase predicts coronaryheart disease events: a 10-year follow-up of the Hoorn study.Atherosclerosis 2007;191:391–396.

[11] Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G,Bellentani S. Prevalence of and risk factors for nonalcoholic fattyliver disease: the dionysos nutrition and liver study. Hepatology2005;42:44–52.

doi:10.1016/j.jhep.2008.05.003

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