Journal of MAY 2012 • Vol. 4 • No. 3 the Society of ... · this adage more important than...

MAY 2012 • Vol. 4 • No. 3

Journal of the Society of PhySicianS of hong Kong

ISSN 2072-4209

executive committee

PRESIDENT

Dr Lam tat chung, Paul 林達聰醫生

VIcE PRESIDENT

Dr tsang Wah tak, Kenneth曾華德醫生

HoN. SEcRETaRy

Dr Shiu cho tak, Wesely邵祖德醫生

cHIEF EDIToR

Dr Lau chu Pak 劉柱柏醫生

eDitoRS

Dr chan hin Lee, henry 陳衍里醫生

Dr chan Kwok Wing, fredriech 陳國榮醫生

Dr chan Pui yiu, nicola 陳珮瑤醫生

Dr chan tak hin 陳德顯醫生

Dr chen yi tin 陳以天醫生

Dr Kung Wai chee, annie龔慧慈醫生

Dr Lam tat chung, Paul 林達聰醫生

Dr Lam cheung cheung, Barbara藍章翔醫生

Professor Leung Wai Keung 梁偉強教授

Dr ng fook hong 吳福康醫生

Dr Shiu cho tak ,Wesely 邵祖德醫生

Dr tsang Wah tak, Kenneth 曾華德醫生

Dr Wong chun yu, Benjamin 王振宇醫生

CONTENTS

29 Primary Prevention of Sudden cardiac Death Dr Kathy Lee (李麗芬醫生);

Professor Lau Chu Pak (劉柱柏教授)

30 hypertension and atrial fibrillation Dr Siu Chung Wah, David (蕭頌華醫生)

33 the Role of combination therapy in the management of hypertension

Dr Miao Hu, Teresa (胡淼博士); Professor Brian Tomlinson (湯寧信教授)

37 non-alcoholic fatty Liver Disease Dr Ng Fook Hong (吳福康醫生)

41 management of chronic hepatitis B infection – Diagnosis

Dr Lui Yan Ni (呂恩妮醫生)

www.sophysicianshk.orgVisit the web site for our monthly CME programmes for doctors

香港內科學會THE SOCIETY OF PHYSICIANS OF HONG KONG

The loss of p53 functions, either through mutations on the p53 gene itself or other factors, has long been associated with decreased radiosensitivity of human tumor cells. For example, patients with recurrent non-small cell lung carcinoma (NSCLC ) whose tumors were found with mutations in exons 5-8 of the p53 gene were up to four times less likely to respond to radiotherapy than those patients whose tumors had wild-type p53.1 Similarly, analysis of glioblastoma multiforme brain tumor (GM) clonogenic cell l ines has indicated that the lack of functional p53 was associated with resistance to fractionated irradiation.2 A closer look at the phenomenon suggests that tumor cells that retain radiation-induced G1 arrest and radiation-induced accumulation of p53 levels are those that show the highest sensitivity to ionizing radiation.3 Simultaneous detection of bcl-2 over-expression and p53 gene mutations in primary squamous-cell carcinoma of the head and neck (HNSCC) treated with conventional radiotherapy is associated with higher risk of locoregional failure and worse survival within 5 years.

Many such examples have pointed to a mechanism whereby tumor cells have become ionizing radiation-resistant because mutations in their p53 fail to induce cell death by apoptosis, or tumor cells have acquired other anti-apoptosis me ch a nisms su ch a s w h e n b c l - 2 i s expressed at high levels. As in normal cells, irradiated tumor cells seem to have the choice between dying by apoptosis and undergoing growth arrest, a process that seems to be dictated by the severity of DNA damage, and type of tissue (see review).4 When tumor cells lose p53 functions, they revert to growth arrest that give the cells a chance to repair DNA damage, and perhaps die by mitotic catastrophe if the damage cannot be repaired.5

The idea that supplementing tumor c e l l s w i t h e xo g e n o u s p 5 3 b y v i r a l vector transduction would increase radiosensitivity, or equivalently, reverse radioresistance, has been tested in both

pre-clinical and clinical settings by various groups. Indeed, human prostate cancer cell lines have been shown to become highly sensitive to ionizing radiation upon infection with an adenoviral vector containing the wild-type p53 in a viral dose-dependent manner, which also resulted in induction of G1 cell cycle arrest.6 Growth of human cervical cancer cells have also been shown to be inhibited by a combination of ionizing radiation and p53 added by viral transduction at a rate that was significantly higher than when the cells were treated by either method alone. 7

In a clinical study involving patients with advanced nasopharyngeal carcinoma (NPC), 42 subjects who were treated with a combination of adenoviral p53 gene therapy by intratumoral injection and local treatment with radiotherapy showed remarkable complete tumor response rate of 2.73 times higher than those 40 control patients who received radiotherapy alone.8 In addition, locoregional recurrence observed in follow-ups over a period of 6 years in the combination treatment group was only 2.7% compared to 28% for the group that received radiotherapy alone. Thus, at least for this study treatment of tumors in patients who received both gene therapy and radiation showed not only rapid complete tumor response but also long-term inhibition of local recurrence.

Solid tumors are complex structures involving heterogeneous types of tumor cells, stromal cells that support structure, endothelial cells that are involved in i ts vasculature, infiltrat ing immune cells of various kinds that are likely is suppressed state, and a subpopulation of cancer stem cells (CSCs). In particular, the CSCs have caught the attention of many investigators for they seem to be involved in resistance to genotoxic treatments, in the repopulation of the tumor mass, and in distant metastases (see review).9 Certain studies show that p53 is highly involved in the suppression of CSCs10 11 and that perhaps loss of p53 could lead to genetic instability, which in turn results in plasticity, a hallmark of

CSCs, of certain phenotypes in the tumor population due to random mutations and clonal evolution.12 Loss of p53 and deregulation of growth factor signalling pathways are thought be involved in the transformation of adult neural stem cells, and it is suggested treatments involving reactivation of p53 in brain tumor stem cell populations should be explored.13 In breast cancers, studies show that tumor cells can acquire stem cell properties when p53 functions are lost.14 As the focus in cancer treatment is turning towards the control of CSCs in which p53 seems to be central in its regulation, it is perhaps time to reconsider the role of p53 gene therapy in combination with conventional treatments in the development of highly effective regimens for various types of solid tumors.

Tumor Radioresistance and p53: Focusing on Cancer Stem CellsBy D. S. Bautista, Ph.D.

Modecs Genetics, Inc. (Toronto)

D. Matsuzoe (2009). P53 mutations predict non-small cell lung carcinoma response to radiotherapy. Cancer Letters 135:189-914.D. Hass-Kogan, S. Kogan, G. Yount, J. Hsu, M. Haas, D. Deen, and M. Israel (2009). P53 function influences the effect of fractionated radiotherapy on glioblastoma tumors. Intl J Radiation OncoBiologyPhysics 43:399-403.A.J. McIlwrath, P.A. Vasey, G.M. Ross, and R. Brown (1994). Cell cycle arrests and radiosensitivity of human tumor cell lines: Dependence on wild-type p53 for radiosensitivity. Cancer Research 54:3718-3722.A.V. Gudkov and E.A. Komarova (2003). The role of p53 in determining sensitivity to radiotherapy. Nature Reviews Cancer 3:117-129.A.V. Gudkov and E.A. Komarova, op. cit.R. Sasaki, T. Shirakawa, Z. Zhang, A. Tamekane, A. Matsumoto, K. Sugimura, M. Matsuo, S. Kamidono, and A. Gotoh (2009). Additional gene therapy with Ad5CMV-p53 enhanced the efficacy of radiotherapy in human prostate cancer cells. Intl J Radiation OncoBiologyPhysics 51:1336-1345.J.J. Huh, J.K. Wolf, D.L. Fightmaster, R. Leutan, and M. Follen (2003). Transduction of adenovirus-mediated wild-type p53 after radiotherapy in human cervical cancer cells. Gynecologic Oncology 89:243-250.J.J. Pan, S.W. Zhang, C.B. Chen, S.W. Xiao, Y. Sun, C.Q Liu, X. Su, D.M. Li, G. Xu, B. Xu, and Y.Y. Lu (2009). Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol 27:799-804. C.T. Jordan, M.L. Guzman, and M. Noble (2006). Cancer stem cells. N Eng J Med 355:1253-61.M. Zhang, F. Behbod, R.L. Atkinson, M.D. Landis, F. Kittrell, D. Edwards, D. Medina, A. Tsimelzon, S. Hilsenbeck, J.E. Green, A.M. Michalowska, and J.M. Rosen

mouse model of breast cancer. Cancer Res 4674-82.S. Godar, T.A. Ince, G.W. Bell, D. Feldser, J.L. Donaher, J. Bergh, A. Liu, K. Miu, R.S. Watnick, F. Reinhardt, S.S. McAllister, T. Jacks, and R.A. Weinberg (2008). Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134:62-73.D.J. Jerry, L. Tao, H. Yan (2008). Regulation of cancer stem cells by p53. Breast Cancer Res 10:304S-M Hede, I. Nazarenko, M. Nister, M.S. Lindstrom (2010). Novel perspectives on p53 function in neural stem cells and brain tumors. J Oncol 2011:1-11.H. Mizuno, B.T. Spike, G.M. Wahl, and A.J. Levine (2010). PNAS USA 107:22745-22750.

References:1.

2.

3.

4.

5.6.

7.

8.

9.

10.

11.

12.

13.

14.

All enquiries / further assistance, please contact: Joel C gnaW anailuJ / gneh C 9922 6853 )258( :enohpeleT tcatno

Email: [email protected] ; [email protected]: www.modecsgenetics.com

Information provided by Modecs Genetics Inc. Toronto, Canada. Not reviewed by the Editorial Board.

In medicine, prevention is better than cure, and in no field is this adage more important than cardiovascular (CV) disease. Hypertension is a major CV risk factor, and in this issue, Pro-fessor Tomlinson and Professor Siu explore its implications for patient management and atrial fibrillation (AF). Early use of anti-hypertensive combination therapy can significantly enhance ef-ficacy and reduce side effects. The role of optimal hypertension treatment to prevent AF is controversial, and is of great im-portance as AF leads to stroke and heart failure. Dr Kathy Lee summarizes the latest guidelines for preventing sudden cardiac death, particularly in patients with prior myocardial infarction and left ventricular dysfunction. Also in this issue, Dr Ng and Dr Lui review the early diagnosis and prevention of fatty liver disease and hepatitis B. Both are common problems encountered by practising physicians.

Dr lau Chu Pak劉柱柏醫生FRCP, MD, FHKAM (Medicine)Chief Editor

Dr lam Tat Chung, Paul林達聰醫生FRCP, FHKAM (Medicine) FRCPsych, FHKAM (Psychiatry)President

editorial

editorial office:UBM Medica 27th Floor, OTB Building, 160 Gloucester Road, Wan Chai, Hong KongT +852 2559 5888 F +852 2559 6910

advertising enquiries:Ms Chloe WongT +852 2155 8557e-mail: [email protected]

© 2012 The Society of Physicians of Hong Kong. All rights reserved. No part of this publication may be reproduced in any language, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the written consent of the copyright owner. Permission to reprint must be obtained from the publisher. Advertisements are subject to editorial acceptance and have no influence on editorial content or presentation. The Society of Physicians of Hong Kong does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature.

Pictorial Medical History (2)

Dr lam Tat Chung, Paul (林達聰醫生)FRCP, FRCPsych, FHKAM (Medicine), FHKAM (Psychiatry)Specialist in Psychiatry (Private Practice)Honorary Clinical Assistant Professor, University of Hong Kong.

Nowadays, the bronze snake of Moses motif rarely

appears in the emblems of medical institutions. The Royal

Society of Medicine (RSM) in the United Kingdom is one ex-

ception. The RSM coat-of-arms depicts a single snake en-

twined around a T-shaped rod; this rod is also known as the

Tau cross, which the Old Testament uses interchangeably

with the Christian cross. Certain religious orders, such as

the Franciscans, use the Tau cross as their insignia and it is

depicted on their gowns. The green colour on the RSM crest

represents medicine and red represents surgery.

coat-of-arms of the Royal Society of medicine, uK

tau, shaped like a capital t, is a letter in the greek and hebrew alphabets.

Journal of The Society of Physicians of Hong Kong 29

Primary prevention of sudden cardiac death involves prophy-lactic intervention in individuals with no history of spontaneous

life-threatening arrhythmias. The mechanism of sudden death is most likely acute myocardial infarction (MI) with plaque rupture, which results in ventricular fibrillation or other fatal com-plications. The main strategies to prevent sudden death should be prevention, early diagnosis and timely treatment of coronary artery disease. Pharmacological agents, such as antiplatelet agents and statins for plaque stabilization, decrease coronary death and sudden deaths. Large-scale randomized clinical trials have shown that implantable cardio-verter-defibrillator devices (ICDs) also decrease mortality, particularly sudden cardiac deaths.

The American College of Cardio-logy, the American Heart Association and the Heart Rhythm Society published the latest guidelines on using ICDs in 2008. Primary prevention is indicated in patients with prior MI, New York Heart Association (NYHA) Class I and left ven-tricular (LV) ejection fraction 0.30 or less. Prophylactic ICDs are indicated for:• Patients with prior MI, NYHA Class II

or III, and LV ejection fraction of 0.35 or less.

• Patients with non-ischaemic heart failure with NYHA Class II or III symptoms, and LV ejection fraction of 0.35 or less.

• Certain conditions known to be asso-ciated with high risk of sudden death, when symptoms or risk markers are present; for example, long-QT syndrome, Brugada syndrome, hyper- trophic cardiomyopathy, and arrhyth-mogenic right-ventricular cardiomyopathy.

Patients with structural heart disease, notably previous MI or LV dys-function, are at risk of sudden death. A major problem in preventing sudden death is the lack of accurate and reliable ways to identify most at-risk individuals in whom an ICD would be of greatest benefit. So far, only LV ejection fraction and inducibility during programmed elec-trical stimulation have demonstrated pre-dictive value in risk stratification. Other non-invasive strategies, including signal-averaged electrocardiography, microvolt T wave alternans and heart rate turbulence, have not proven discriminatory in patient selection. Primary prevention is both costly and demanding in technical com-plexity, with a number-needed-to-treat in primary prevention clinical trials that ranges from 8 to 20. Ongoing ICD trials are evaluating various risk assessment strategies designed to make prophylactic ICD more cost-effective. Future clinical trials may also identify other high risk populations that may benefit from pro-phylactic ICD.

Although patients with mild coronary disease and normal systolic function have only modestly increased mortality, they account for a major pro-portion of sudden deaths, because many individuals have this condition and so constitute a much bigger denominator. However, the overall population risk should be low and prophylactic device implantation is not practical.

The availability of public-access automated external defibrillators and personnel trained in cardiopulmonary resuscitation are both important to im-proving outcomes in out-of-hospital cardiac arrest. Heart-health education and increased awareness of heart diseases are also essential to combat sudden death in the community.

Primary Prevention of Sudden cardiac Death

Key words: Sudden cardiac death (心臟猝死), Implantable cardioverter-defibrillator (植入式心臟除顫器), coronary artery disease (冠心病)

Dr Kathy lee (李麗芬醫生)

Specialist in Cardiology MBBS, MRCP (UK) FRCP (Edin) FHKCP, FHKAM (Med)

Honorary Clinical Assistant Professor Department of Medicine University of Hong Kong

Professor lau Chu Pak (劉柱柏教授)

Specialist in Cardiology MD, MRCP (UK), FRCP (Edin, Glas, Lond) FRACP, FHKCP, FHKAM (Medicine), MBBS

Honorary Clinical Professor Department of Medicine University of Hong Kong

30 Journal of The Society of Physicians of Hong Kong

Introduction

Elevated blood pressure (BP), termed hypertension, is the principal and most prevalent risk factor for atrial fibrillation (AF),1

and is the most common co-morbidity in AF patients.2 The increasing prevalence of hypertension3 and AF4 worldwide due to population aging, contributes to stroke, heart failure and overall mortality.5 However, it remains unclear whether or not treating hypertension prevents AF or reduces the risk of AF related compli-cations. This article reviews the epide-miology and therapeutic implications of AF in hypertensive patients.

Epidemiology

Approximately 1% of the overall popu-lation has AF.6 With increasing population ageing, the total number of AF patients is expected to increase by two to three times over the next 20–30 years.7 Re-cently, the Atherosclerosis Risk in Com-munities (ARIC) study confirmed that common cardiovascular risk factors, including tobacco smoking, diabetes mellitus, hypertension, overweight/obesity and prior cardiac disease, con-tribute to 57% of incident AF.8 Among these risk factors, elevated or borderline BP was the most important contributor, accounting for 20–25% of AF.

Pathophysiology

Despite the association between hyper-tension and AF, the pathophysiological link remains unclear. To date, two major mechanisms have been proposed: 1) Haemodynamic changes in the atria due to hypertension; and 2) Activation of the renin-angiotensin-aldosterone system (RAAS).

Hemodynamic Changes in AtriaIn long-standing hypertension, the

excessive after-load imposed on the left ventricle leads to progressive thickening of the left-ventricular wall and left-ven-tricular hypertrophy (LVH). The increased left-ventricular stiffness and diastolic and systolic dysfunction accompanying LVH inevitably raise left-atrial pressure.9 This chronic atrial stretch results in pro-gressive left-atrial enlargement, with decreased atrial contractility and increased atrial compliance. Left-atrial enlargement and mechanical dysfunction10 are all important predictors of AF.

Renin-angiotensin-aldosterone System ActivationEmerging evidence suggests that RAAS activation contributes to AF. Experimental studies have demonstrated that angio-tensin II induces atrial fibrosis and hyper-trophy, causes changes in expression of ion channels, gap junction and calcium handling, as well as increasing oxidative stress and inflammation.11,12

Therapeutic Implications

The pathophysiological links between hypertension and AF offer opportunities for therapeutic intervention to prevent AF in hypertensive patients. Effective BP control per se may be one of the most important ways to prevent AF, by reducing left-atrial enlargement and LVH.12-15 Fur-thermore, it is well known that despite comparable BP lowering effects, anti-hypertensive agents that block RAAS appear to be more effective than those that do not in reversing LVH,16 and thus preventing AF.

Primary Prevention of AF by RAAS Inhibition

A retrospective analysis by the USA drug administration, which suggested that an-giotensin conversion enzyme inhibition (ACEI) decreased the risk of AF by 15%

hypertension and atrial fibrillation

Dr Siu Chung Wah, David (蕭頌華醫生)

MBBS (HKU), MD (HKU), MRCP (UK) FHKCP, FHKAM

Associate Professor Department of Medicine The University of Hong Kong

Honorary Consultant Queen Mary Hospital

Key words: atrial fibrillation (心房顫動), Hypertension (高血壓), Management (治理)


over 4.5 years compared with a calcium channel blocker (CCB), provided the earliest evidence supporting therapeutic RAAS inhibition to prevent new AF.17 Recent clinical trials on angiotensin re-ceptor blockers (ARBs) showed more con-sistently beneficial effects in preventing AF. In the secondary analysis of the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study,18 losartan reduced new AF by 33% compared with atenolol (3.5% vs. 5.3%, p<0.001). In the Valsartan Antihypertensive Long-term Use Evaluation Trial (VALUE), a valsartan-based regimen reduced new AF by 16% compared with an amlodipine-based regimen.19 In both studies, the prevention of AF appears to exceed that expected from BP control alone. Furthermore, a nested case-control study in UK also demonstrated that treatment with ACEI-based and ARB-based regimens was as-sociated with a 25–29% reduction in AF compared with CCB-based regimens.20 In meta-analyses, ACEIs and ARBs had similar overall benefit for AF prevention, but there are no head-to-head data.21 Com-paring LIFE versus VALUE suggests that ARB is more beneficial than a CCB for pre-venting AF in hypertensive patients with LVH. Indeed, recent European Society of Cardiology guidelines recommend that ACEIs and ARBs should be considered for preventing new AF in patients with hyper-tension, particularly those with LVH (Class IIa, level B).22 In patients with uncom-plicated hypertension, optimal BP control with any effective anti-hypertensive drugs, rather than a specific class, to prevent LVH and left-atrial enlargement appears to be more important to prevent AF.

Secondary Prevention with RAAS Inhibition

Currently, there are very limited data to support using ACEIs or ARBs for secondary prevention of AF in pa-tients with hypertension. The Gruppo Italiano per lo Studio della Soprav-vivenza nell’Insufficienza cardiaca Atrial Fibrillation (GISSI-AF)23 was the largest secondary prevention study, involving 1,442 patients with either paroxysmal or recently cardioverted persistent AF.

Up to 85% of patients in GISSI-AF had hypertension, and there was no significant reduction in AF recurrence between pa-tients randomized to valsartan versus placebo. Likewise, the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) II study24 showed no re-duction in AF recurrence with candesartan versus amlodipine, as monitored by daily transtelephonic electrocardiogram re-cording in 318 hypertensive patients with paroxysmal AF. Moreover, in the Atrial fi-brillation Clopidogrel Trials with Irbesartan for prevention of Vascular Events-Irbe-sartan (ACTIVE I) trial, irbesartan did not reduce the risk of AF recurrence in par-oxysmal AF patients (n=1730) who were in sinus rhythm on enrollment.25 Overall, these studies suggest that neither ACEIs nor ARBs alone prevent arrhythmic re-currence in hypertensive patients with paroxysmal AF or those with persistent AF after cardioversion. It is therefore possible that ACEIs and ARBs cannot prevent progression of AF in individuals who have significant atrial remodeling.

Conclusions

Hypertension is the most common at-tributable risk factor for the increasing population burden of AF. Both clinical and experimental studies have demonstrated a close pathophysiological link between AF and hypertension. While optimal BP control with antihypertensive agents in hypertensive patients may potentially reduce the risk of AF, the promise of RAAS blockade with ACEIs and ARBs for primary and secondary prevention of AF remains unproven. Further randomized studies are needed to define the optimal antihypertensive agents for preventing AF recurrence and progression.

References:1. Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial

fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–844.

2. Le Heuzey JY, Breithardt G, Camm J, et al. The RecordAF study: design, baseline data, and profile of patients according to chosen treatment strategy for atrial fibrillation. Am J Cardiol 2010;105:687-693.

3. Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hyper-tension. Global burden of blood-pressure-related disease, 2001. Lancet 2008;371:1513-1518.

4. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibril-lation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-2375.

5. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibril-lation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946-952.

6. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N-9N.

7. Hobbs FD, Fitzmaurice DA, Mant J, et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health Technol Assess 2005;9:1-74.

8. Huxley RR, Lopez FL, Folsom AR, et al. Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2011;123:1501-1508.

9. Schotten U, Verheule S, Kirchhof P, et al. Pathophysiological mech-anisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011;91:265-325.

10. Toh N, Kanzaki H, Nakatani S, et al. Left atrial volume combined with atrial pump function identifies hypertensive patients with a history of paroxysmal atrial fibrillation. Hypertension 2010;55:1150-1156.

11. Goette A, Lendeckel U. Electrophysiological effects of angiotensin II. Part I: signal transduction and basic electrophysiological mechanisms. Europace 2008;10:238-241.

12. Savelieva I, Kakouros N, Kourliouros A, et al. Upstream therapies for management of atrial fibrillation: review of clinical evidence and impli-cations for European Society of Cardiology guidelines. Part I: primary prevention. Europace 2011;13:308-328.

13. Okin PM, Wachtell K, Devereux RB, et al. Regression of electrocar-diographic left ventricular hypertrophy and decreased incidence of new-onset atrial fibrillation in patients with hypertension. JAMA 2006;296:1242-1248.

14. Wachtell K, Gerdts E, Aurigemma GP, et al. In-treatment reduced left atrial diameter during antihypertensive treatment is associated with reduced new-onset atrial fibrillation in hypertensive patients with left ventricular hypertrophy: The LIFE Study. Blood Press 2010;19:169-175.

15. Hennersdorf MG, Schueller PO, Steiner S, et al. Prevalence of par-oxysmal atrial fibrillation depending on the regression of left ventricular hypertrophy in arterial hypertension. Hypertens Res 2007;30:535-540.

16. Klingbeil AU, Schneider M, Martus P, et al. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003;115:41-46.

17. L’Allier PL, Ducharme A, Keller PF, et al. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol 2004;44:159-164.

18. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hyper-tension (LIFE) study. J Am Coll Cardiol 2005;45:712-719.

19. Schmieder RE, Kjeldsen SE, Julius S, et al. Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial. J Hypertens 2008;26:403-411.

20. Schaer BA, Schneider C, Jick SS, et al. Risk for incident atrial fibrillation in patients who receive antihypertensive drugs: a nested case-control study. Ann Intern Med 2010;152:78-84.

21. Schneider MP, Hua TA, Bohm M, et al. Prevention of atrial fibrillation by renin-angiotensin system inhibition a meta-analysis. J Am Coll Cardiol 2010;55:2299-2307.

22. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369-2429.

23. Disertori M, Latini R, Barlera S, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;360:1606-1617.

24. Yamashita T, Inoue H, Okumura K, et al; J-RHYTHM II Investigators. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study). Europace 2011;13:473-479.

25. Yusuf S, Healey JS, Pogue J, et al. Irbesartan in patients with atrial fibril-lation. N Engl J Med 2011;364:928-938.

“Effective BP control per se may be one of the most important ways to

prevent AF”


The prevalence of hypertension continues to rise in most regions of the world, despite better un-derstanding of the predisposing

factors, largely fueled by increasing rates of obesity. Hypertension is often considered the most important cardio-vascular risk factor,1 because it is not only prevalent, but also contributes to large population-attributable fractions of mortality from coronary heart disease and both haemorrhagic and ischaemic stroke.2 Furthermore, although there are several generally-available international guidelines and effective medications for appropriate management of hypertension, the proportion of patients reaching the recommended blood pressure targets is disappointingly small. In the United States, the control of hypertension in-creased from 27.3% in 1988–1994 to 50.1% in 2007–2008;3 however, this sit-uation clearly remains suboptimal and is worse in many other countries.

Appropriate lifestyle advice for all hypertensive patients is essential. Nevertheless, drug therapy should not be delayed unduly in high-risk patients while waiting for lifestyle changes to take effect. Hypertension guidelines em-phasize that most patients will require more than one drug to achieve adequate blood pressure control; if pre-treatment blood pressure is more than 20/10 mmHg above target or there is a high overall level of cardiovascular risk, it is desirable to start treatment with a two-drug com-bination.4,5 In patients with mild hyper-tension and low/moderate cardiovascular risk, treatment can commence at a low dose of a single drug, but in other cases using a low-dose dual combination is ad-visable.5 Moreover, if the starting dose of a single drug does not control blood pressure adequately, it is more effective to add a low dose of a second drug with a complementary mechanism of action, than to double the dose of the initial drug. In a meta-analysis of 354 trials of

common antihypertensive drug classes, all five categories produced similar effects, with average blood pressure reductions of 7.1/4.4 mmHg at half-standard doses and 9.1/5.5 mmHg at the standard doses.6 Doubling the standard dose had little additional affect, whereas adding a second complementary drug reduced blood pressure by an average 14.6/8.6 mmHg, which was close to an additive effect. Figure 1 shows appro-priate combinations of different classes of antihypertensive drugs. The 2009 reappraisal of the European guidelines on hypertension management additionally advised that an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) combined with a diuretic or a calcium channel blocker (CCB) were either supported by recent large-scale trials or appeared to be rational and effective, and are therefore favoured first-line options.7 The use of fixed-dose or single pill combinations may be pref-erable, because simplifying treatment improves compliance with therapy.

Dihydropyridine CCBs have become very popular antihypertensives, because they are effective in most patients and have few contraindications. A recent large meta-analysis found that CCBs prevented stroke to a greater extent than the other main antihypertensive drug classes.8 Am-lodipine is one of the most popular CCBs; its very long plasma elimination half-life yields prolonged duration of action and persisting antihypertensive effects even with missed doses.9 Outcomes in trials of amlodipine have been favourable compared to alternative anti-hypertensive regimens; for example, the overall outcome with amlodipine-based therapy in ALLHAT (The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial), was similar to that with lisinopril-based therapy and was better for some endpoints, notably stroke.10

It is logical to combine a CCB with a renin-angiotensin-aldosterone system

the Role of combination therapy in the management of hypertension

Key words: Hypertension (高血壓), combination therapy (合併療法), angiotensin receptor blockers (血管緊張素受體拮抗劑).

Dr Miao Hu, Teresa (胡淼博士)

BSc, PhD

Postdoctoral Fellow Department of Medicine and Therapeutics Chinese University of Hong Kong Prince of Wales Hospital Shatin, Hong Kong

Professor Brian Tomlinson (湯寧信教授)

BSc, MBBS, MD, FRCP (Lond, Edin, Glasg) FACP, FHKCP, FCP, FHKAM (Med) Specialist in Internal Medicine

Head, Division of Clinical Pharmacology Department of Medicine and Therapeutics Chinese University of Hong Kong Prince of Wales Hospital Shatin, Hong Kong


(RAAS) inhibitor, to overcome the counter-regulatory effects that result in increased plasma renin activity, and also to provide complementary clinical benefits (Figure 2). CCBs have not been shown to reduce mortality and morbidity associated with heart failure or renal disease, whereas some ACEIs and ARBs appear to have these benefits. Few clinical trials have compared different combination therapy regimens; however, in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial, com-bining the ACEI benazepril with amlo-dipine was superior to its combination with hydrochlorothiazide in reducing cardiovascular events in high-risk hyper-tensive patients, despite having a similar effect on blood pressure.11 This may suggest that a RAAS inhibitor and CCB combination is better than CCB combined with a diuretic.

ACEIs have many clinical ad-vantages, including reducing cardio-vascular events in high-risk patients, as shown with ramipril in the HOPE (Heart Outcomes Prevention Evaluation) study.12 Although generally well-tolerated, ACEIs do have the side effect of irritating dry cough, which probably occurs more commonly than has been reported and is certainly frequent in some Asian popu-lations. ACEI-induced cough may lead 5% or more of patients to discontinue therapy.13 In a study of patients who received initial antihypertensive mono-therapy, those prescribed ACEIs had the lowest discontinuation rate, except for those started on ARBs.14 Adherence to long-term treatment is obviously im-portant in managing hypertension and is influenced by several factors in addition to the tolerability of individual drugs. A systematic review reported that sim-plifying dosing regimens increased relative adherence by 8% to 19.6%.15 In a large Italian study of newly diagnosed hypertensive patients, antihypertensive combination therapy was one of the factors associated with high adherence, and highly-adherent patients had signifi-cantly fewer cardiovascular events than those with poorer adherence.16

The ARBs are all well-tolerated, but differ in certain pharmacological re-spects (Table 1). Comparing pharma-

Thiazide diuretics

ACE inhibitors

Calcium antagonists

β-blockers

α-blockers

Angiotensin receptor antagonists

CCB• Arteriodilation• Peripheral oedema• Effective in low-renin patients• Reduces cardiac ischaemia

ARB• Venodilation• Attenuates peripheral oedema• Effective in high-renin patients• No effect on cardiac ischaemia

ARB• RAAS blockade• CHF and renal benefits

CCB• RAAS activation• No renal or CHF benefits

BP

Synergistic BP reduction

Complementary clinical benefits



BP

CCBs produce counter-regulatory

effects

Thiazide diuretics

ACE inhibitors

Calcium antagonists

β-blockers

α-blockers

Angiotensin receptor antagonists


ARB• Venodilation• Attenuates peripheral oedema• Effective in high-renin patients• No effect on cardiac ischaemia

ARB• RAAS blockade• CHF and renal benefits


BP

Synergistic BP reduction

Complementary clinical benefits



BP

CCBs produce counter-regulatory

effects

figure 1. Recommended dual-drug combinations for treating hypertension.

figure 2. complementary benefits of combined calcium channel blocker plus angiotensin receptor blocker.

The drugs outlined by frames have proven beneficial in controlled intervention trials. Drug classes joined by continuous lines are recommended in combination therapy. The drug classes joined by red lines were recommended for priority use in the 2009 reappraisal. The bold dashed line joining beta-blockers and diuretics is used because these combinations can improve clinical outcomes, but in some cases will increase the risk of developing diabetes and so have not been recommended.

Adapted from reference 5 and 7.

A) Calcium channel blockers (CCBs) produce peripheral oedema and counter-regulatory effects with activation of the renin-angiotensin-aldosterone system (RAAS). B) RAAS activation and peripheral oedema can be reduced by combining CCBs with ARBs and such combinations provide additional clinical benefits.

BP, blood pressure; ARB, angiotensin receptor blocker; CHF, chronic heart failure.

(a)

(B)


cokinetics, telmisartan has the longest plasma elimination half-life, which results in very effective 24-hour blood pressure control, and is highly lipid-soluble with the largest volume of distribution, indi-cating high tissue penetration. In addition, telmisartan is the only ARB shown to ac-tivate peroxisome proliferator-activated receptor-gamma at clinically relevant doses; this effect inhibits vascular tension in resistance arteries by increasing nitric oxide.17 All ARBs are approved for treating hypertension and some for the additional indications of renal disease, heart failure, or left ventricular dysfunction. However, based on the ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study, which showed that telmisartan had similar benefits to ramipril on vascular events and major renal outcomes, telmisartan is the only ARB approved for patients at high car-diovascular risk, including those with type 2 diabetes and target-organ damage.18,19

Fixed-dose ARB plus diuretic com-binations have been available for several years and recently combinations of am-lodipine with some ARBs, including olm-esartan, telmisartan and valsartan have been introduced. These provide very ef-fective and well-tolerated treatment that can be initiated as a first-line option in newly diagnosed patients with moderate to severe hypertension, or those with high overall cardiovascular risk, and do not have adverse effects on the addi-tional risk factors. The contraindications are similar to those of ARBs alone and include pregnancy, hyperkalaemia and severe renal or hepatic impairment. These ARB/CCB combinations are likely to be effective in most patients, irrespective of whether the high blood pressure results

from high salt intake or high plasma renin activity. Combining amlodipine with an ARB has also been found to reduce the side effect of ankle swelling; for instance, combined amlodipine and telmisartan reduced the incidence of peripheral oedema significantly, to 5.2% compared with 17.8% of patients on 10 mg amlo-dipine monotherapy.20

In conclusion, the recent intro-duction of fixed-dose amlodipine plus ARB combination tablets provides a new option for initiating antihypertensive treatment or for switching from other combination regimens to reduce the number of tablets taken per day, which should improve ad-herence to long-term drug therapy. These combinations have synergistic mech-anisms of action and complementary clinical indications, and are extremely well-tolerated with few contraindications. Consequently, their use should help more patients to achieve the blood pressure targets that current guidelines recommend and eventually reduce the overall mortality and morbidity related to coronary heart disease and stroke.

References1. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected

major risk factors and global and regional burden of disease. Lancet 2002;360:1347-1360.

2. Martiniuk AL, Lee CM, Lawes CM, et al. Hypertension: its prevalence and population-attributable fraction for mortality from cardiovascular disease in the Asia-Pacific region. J Hypertens 2007;25:73-79.

3. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA 2010;303:2043-2050.

4. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.

5. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hy-pertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-1187.

6. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combi-nation treatment with blood pressure lowering drugs: analysis of 354 randomised trials. Br Med J 2003;326:1427.

7. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hyper-tension Task Force document. J Hypertens 2009;27:2121-2158.

8. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 ran-domised trials in the context of expectations from prospective epidemio-logical studies. Br Med J 2009;338:b1665.

9. Tomlinson B, Woo J, Thomas GN, Chau YM, Critchley JA. Randomized, controlled, parallel-group comparison of ambulatory and clinic blood pressure responses to amlodipine or enalapril during and after treatment in adult chinese patients with hypertension. Clin Ther 2004;26:1292-1304.

10. Leenen FH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension 2006;48:374-384.

11. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-2428.

12. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.

13. Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians’ Desk Reference. Am J Med 2010;123:1016-1030.

14. Corrao G, Zambon A, Parodi A, et al. Discontinuation of and changes in drug therapy for hypertension among newly-treated patients: a popu-lation-based study in Italy. J Hypertens 2008;26:819-824.

15. Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med 2004;164:722-732.

16. Mazzaglia G, Ambrosioni E, Alacqua M, et al. Adherence to antihy-pertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation 2009;120:1598-1605.

17. Yuen CY, Wong WT, Tian XY, et al. Telmisartan inhibits vasoconstriction via PPAR{gamma}-dependent expression and activation of endothelial nitric oxide synthase. Cardiovasc Res 2011;90:122-129.

18. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53.

19. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559.

20. Littlejohn TW, 3rd, Majul CR, Olvera R, et al. Results of treatment with telmisartan-amlodipine in hypertensive patients. J Clin Hypertens (Greenwich) 2009;11:207-213.

table 1. Pharmacokinetic properties and approved indications of the angiotensin receptor blockers.

Drug Losartan (e3174) valsartan irbesartan candesartan cilexetil

telmisartan eprosartan olmesartan medoxomil

Bioavailability (%) 33 10–35 60–80 15 40–60 13 26–29

Half-life (hours) 1–3 (6–9) 6–9 11–15 5–9 20–38 20 10–15

Volume of distribution (L) 34 (12) 17 53–93 0.13 L/kg 500–2000 308 17

Trough-peak ratio (%) 65 54–76 60–70 76–87 66–100 65-80 (b.i.d dosing)

60–80

Approved indications HT, DN, reducing risk of stroke in HT

with LVH

HT, heart failure HT, DN HT, heart failure HT, reducing high cardiovascular

risk

HT HT

E3174, active metabolite of losartan; DN, diabetic nephropathy; HT, hypertension; LVH, left ventricular hypertrophy.

“The recent introduction of

fixed-dose amlodipine plus ARB combination tablets provides a new

option for initiating antihypertensive

treatment”


Introduction

Non-alcoholic fatty liver disease (NAFLD) is a clinico-histopatho-logical diagnosis. Although the histological features resemble

alcohol-induced liver injury, patients have little or no history of alcohol consumption. The histological spectrum ranges from fat accumulation in hepatocytes without con-comitant inflammation or fibrosis (simple hepatic steatosis), to hepatic steatosis with a necroinflammatory component (steatohepatitis) that may or may not have associated fibrosis. Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD, with hepatocellular injury that may progress to fibrosis, cirrhosis and hepatocellular carcinoma in 50%, 15% and 4% of patients, respectively.2 NASH is now recognized as a leading cause of cryptogenic cirrhosis.3

The pathogenesis of NAFLD is likely to result from obesity-related insulin re-

sistance and additional oxidative injury. Hepatic steatosis is a manifestation of excessive triglyceride accumulation in the liver; this can be due to excessive importation of free fatty acids (FFA) from adipose tissue, diminished hepatic export of FFA (secondary to reduced synthesis or secretion of very-low-density lipoprotein), or from impaired beta-oxidation of FFA. Both elevated peripheral fatty acids stored in adipose tissue and fatty acids newly made within the liver contribute to the ac-cumulation of hepatic and lipoprotein fat in NAFLD.4 Insulin resistance is the key mechanism leading to hepatic steatosis and, potentially, steatohepatitis.5-7

Insulin resistance results in im-portant changes in lipid metabolism, such as enhanced peripheral lipolysis, increased triglyceride synthesis and increased hepatic uptake of fatty acids.8 Obesity and type 2 diabetes mellitus (T2DM) are frequently associated with NAFLD. Ad-ditional oxidative injury is required to manifest the necroinflammatory com-ponent of steatohepatitis. FFAs induce several cytochrome P-450 microsomal lipoxygenases that produce hepatotoxic oxygen free-radical species. Increased FFA beta-oxidation and hepatic oxidative stress are present in both NAFLD and NASH, but only NASH is associated with mitochondrial structural defects.5

Epidemiology

NAFLD is the most common liver disorder in Western developed countries, and affects 20–40% of the general popu-lation. In Asia, large population-based surveys in China, Japan and Korea in-dicate that the current prevalence of NAFLD is 12–24%.9 In 2011, a population study in Hong Kong reported the popu-lation prevalence of NAFLD to be 27%; the estimated prevalence of advanced fibrosis in patients with fatty liver in the community was 4%.10 Body mass index and alanine aminotransferase (ALT) level were independent factors associated

with liver stiffness.The major risk factors for NAFLD

are central obesity, T2DM, hyperlipi-daemia and metabolic syndrome. Patients with NASH have prevalences of obesity, T2DM and hyperlipidaemia (hypertriglyc-eridaemia and/or hypercholesterolaemia) of approximately 69–100%, 34–75% and 20–80% , respectively.11,12

Clinical ManifestationsNAFLD or NASH most commonly present as asymptomatic elevation of liver ami-notransferases detected on routine lab-oratory testing. Some patients present with fatigue, malaise and vague right-upper abdominal discomfort.13 Serum aspartate transaminase (AST) and ALT are elevated in 90% of patients, with an AST/ALT ratio usually lower than 1. In contrast, the ratio in alcoholic hepatitis is usually above 2.14,15 Alkaline phosphatase elevation and hyperbilirubinaemia are uncommon. However, amongst patients with NAFLD, normal serum AST or ALT do not exclude the presence of advanced histologic features. Of 51 patients with NAFLD and normal ALT levels, 12 (24%) had bridging fibrosis, whereas 6 (12%) had cirrhosis.16 Diabetes was the only factor independently associated with an increased risk of advanced fibrosis (bridging fibrosis or cirrhosis).

Diagnosis

Ultrasonography is the most common modality used to discose NAFLD, which appears as a hyperechoic texture or bright liver, because of diffuse fatty infiltration.17 Computed tomography (CT) and magnetic resonance imaging (MRI) can identify steatosis.18 However, ultrasonography is not specific, and ultrasonography, CT and MRI are unable to differentiate the histological subtypes of relatively benign non-alcoholic hepatic steatosis or more aggressive NASH.

Transient elastography can accu-rately diagnose advanced liver fibrosis in

non-alcoholic fatty Liver Disease

Key words: Non-alcoholic fatty liver disease (非酒精性脂肪肝)

Dr Ng Fook Hong (吳福康醫生)

MB,BS (HK), MD (HK), MRCP (UK), FRCP (Edinburgh), FRCP (London), FRCP (Glasgow), FHKCP, FHKAM (Medicine)

Specialist in Gastroenterology and Hepatology, Private Practice

Honorary Consultant in Gastroenterology and Hepatology, Ruttonjee Hospital

Honorary Assistant Professor Department of Medicine University of Hong Kong


most NAFLD patients.19 At a cut-off value of 7.9 kPa, the sensitivity, specificity, and positive and negative predictive values for advanced fibrosis (F3 or above) were 91%, 75%, 52%, and 97%, respectively. With high negative predictive value and modest positive predictive value, transient elastography is a useful screening test to exclude advanced fibrosis.

Liver biopsy is not only the sole means of diagnosing NASH defini-tively, but also enables determination of disease severity and may provide insight into prognosis. However, serious compli-cations occur in approximately 1% of pa-tients biopsied,20 with an overall mortality risk of 0.2%.21

Natural History

In a population-based study in the United States, patients with NAFLD had slightly lower overall survival than expected for the general population (standardized mortality ratio of 1.34; 95% confidence interval [CI] 1.00–1.76).22 Higher mor-tality was associated with increasing age (hazard ratio per decade, 2.2; 95% CI, 1.7–2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3–5.2), and cirrhosis (hazard ratio, 3.1; 95% CI, 1.2–7.8). Most mortality was due to cardio-vascular disease, although liver disease accounted for a sizeable minority (14%).23 Recently, a longitudinal study followed up 52 patients (age 44±9 years) with biopsy-proven NAFLD. Liver biopsies were re-peated at month 36.24 Overall, 14 (27%) patients had fibrosis progression, 25 (48%) had static disease, and 13 (25%) had fibrosis regression. Reduction in body mass index and waist circumference was independently associated with nonpro-gressive disease activity and fibrosis.

NAFLD is associated with a high prevalence of colorectal adenomas and advanced neoplasms. In a study con-ducted in Hong Kong, NAFLD patients had a higher prevalence of colorectal adenomas (34.7% vs. 21.5%; p=0.043) and advanced neoplasms (18.6% vs. 5.5%; p=0.002) than healthy controls.25 Adenomas were found more commonly in the right-side colon. Colorectal cancer screening is strongly indicated in this high-risk group.

TreatmentIn patients with NAFLD, the management of comorbidities such as obesity, hyper-lipidaemia and diabetes, is generally rec-ommended. Weight loss and increased physical activity can lead to sustained im-provements in liver enzymes, histology, serum insulin levels and quality of life in patients with NASH. Weight loss should be gradual and should not exceed 1.6 kg per week, since rapid weight reduction has been associated with worsening of portal inflammation and liver fibrosis.26

Liver-protective and anti-inflam-matory drugs to prevent and treat steato-hepatitis and advanced fibrosis may be beneficial.27 Essential phospholipids (EPL) comprise the highly purified fraction of phosphatidylcholine with polyunsat-urated fatty acids in positions C1 and C2, of which 1,2-dilinoleyphosphatidylcholine is the main active ingredient.28 Phosphati-dylcholine is an important structural com-ponent of cellular membranes and helps to break down fats.29 Incorporation of EPL into damaged hepatocyte cell membranes can restore normal membrane structure. EPL has antioxidant activity and protects against lipid peroxidation, is antifibrogenic and reduces transforming growth factor-b1-mediated collagen accumulation in hepatic stellate cells.30 EPL also reduces the interaction between immune effector cells and hepatocytes.31 In a prospective study, EPL significantly improved liver bio-chemistry after 8 weeks and reduced the degree of steatosis, necroinflammation and fibrosis after 6 months.32 No known toxicity or serious side effects have been reported.29 Vitamin E decreases oxidative stress and has therefore been evaluated in patients with NASH. In a randomized controlled study, vitamin E (800 IU daily) was associated with significantly im-proved global histology scores compared with placebo.33 However, mortality was increased in patients who received high-dose vitamin E supplementation (≥400 units/day),34 with an apparent dose-response relationship.

Conclusions

NAFLD is common in Hong Kong. NAFLD is associated with central obesity, T2DM,

hyperlipidaemia and hypertension. The management of these comorbidities is generally recommended. Weight loss and increased physical activity can lead to sustained improvement in liver enzymes, histology, serum insulin levels and quality of life in patients with NASH. Liver- protective and anti-inflammatory drugs to prevent and treat steatohepatitis and ad-vanced fibrosis may be considered. EPL, which have no known toxicity or serious side effects, may be used. High-dose vitamin E supplementation (800 units/day) reduced necroinflammation and ste-atosis, but is not recommended because it is associated with higher mortality.

References1. Ludwig J, Viggiano TR, McGill DB, et al. Non-alcoholic steatohepatitis:

Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-438

2. Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001;21:3-16.

3. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664-669.

4. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115:1343-1351.

5. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steato-hepatitis: association of insulin resistance and mitochondrial abnor-malities. Gastroenterology 2001;120:1183-1192.

6. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin re-sistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373-379.

7. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143:722-728.

8. Kral JG, Lundholm K, Björntorp P, et al. Hepatic lipid metabolism in severe human obesity. Metabolism 1977;26:1025-1031.

9. Chitturi S, Farrell GC, Hashimoto E, et al. Non-alcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol 2007;22:778-787.

10. Wong VW, Chu WC, Wong GL, et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: A population study using proton-magnetic resonance spectroscopy and transient elas-tography. Gut. 2012;61:409-415.

11. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-438.

12. Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonal-coholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74-80.

13. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonal-coholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103-1109.

14. Cohen JA, Kaplan MM. The SGOT/SGPT ratio – An indicator of alcoholic liver disease. Dig Dis Sci 1979;24:835-838.

15. Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonal-coholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999;94:1018-1022.

16. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37:1286-1292.

17. Lonardo A, Bellini M, Tondelli E, et al. Nonalcoholic steatohepatitis and the “bright liver syndrome”: should a recently expanded clinical entity be further expanded? Am J Gastroenterol 1995;90:2072-2074.

18. Rofsky NM, Fleishaker H. CT and MRI of diffuse liver disease. Semin Ultrasound CT MR 1995;16:16-33.

19. Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010;51:454-462.

20. Seeff LB, Everson GT, Morgan TR, et al. Complication rate of per-cutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010;8: 877-883.

21. West J, Card TR. Reduced mortality rates following elective percu-taneous liver biopsies. Gastroenterology 2010;139:1230-1237.

22. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-121.

A complete list of references can be downloaded from www.SOPHYSICIANSHK.org


chronic hepatitis B virus (HBV) infection is a widely prevalent global health problem. Approxi-mately 350–400 million people

worldwide are chronic HBV carriers.1,2 In high prevalent areas such as China, Southeast Asia and Sub-Saharan Africa, as many as 10–15% of the population are chronically infected with HBV. Chronic HBV carriers are at risk of liver cirrhosis, liver failure and hepatocellular carcinoma (HCC),3 and HBV-related diseases are es-timated to account for 500,000–700,000 deaths annually.4

Chronic HBV infection usually follows a characteristic disease course. During the immune tolerance phase, pa-tients are HBV e antigen (HBeAg)-positive and have high serum levels of HBV DNA. However, serum alanine aminotrans-ferase (ALT) levels remain normal with patients having negligible liver damage. The immune clearance phase is charac-terized by elevation of ALT levels, before transiting to the low replication phase,

better known as the ‘inactive carrier state’. In some patients, the immune clearance phase may be protracted. Pro-tracted immune clearance is associated with recurrent hepatitis flares which can result in severe hepatitis, and may be followed by fibrosis and cirrhosis. During the low replication phase, spontaneous HBeAg seroconversion may occur; pa-tients have normal ALT levels and low or normal serum HBV DNA levels.

In approximately 10–20% of in-active carriers, reactivation of HBV repli-cation and exacerbations of hepatitis may occur after years of quiescence (Table).5,6 Therefore, lifelong follow-up with serial testing is necessary to determine the maintenance of a patient’s ‘inactive carrier’ state.

The risk of disease progression to liver cirrhosis and HCC in chronic HBV infection patients is strongly correlated with the viral load. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study conducted in Taiwan demonstrated that the multivariable-adjusted relative risk of HCC increased from 1.1 at HBV DNA levels of 300 to <104 copies/mL to 2.3 at HBV DNA levels of 104 copies/mL to <105 copies/mL, and to 6.1 at HBV DNA levels of >106

copies/mL.7 A further subanalysis of the REVEAL-HBV study revealed that patients with persistently low levels of HBV DNA (300 to <104 copies/mL) were found to have increased risk of developing HCC as compared with those with undetectable levels of HBV DNA (<300 copies/mL).8 The correlation between HBV DNA levels and risk of HCC was independent of age, gender, HBeAg status, presence of liver cirrhosis and viral genotypes.7 Further-more, a direct relationship between the cumulative incidence of cirrhosis and HBV DNA levels was also demonstrated.9 All these findings point to the critical role of viral replication in the progression of liver disease and the subsequent devel-opment of liver-related complications in chronic HBV infection patients. Thus, the primary goal of antiviral therapy is to achieve a durable suppression of viral replication, with the aim of preventing progression of liver diseases – liver cir-rhosis, liver failure and/or HCC – in chronic hepatitis B patients. Current first-line antiviral agents, such as entecavir and tenofovir, have been shown to be effective in achieving and maintaining viral suppression.10-12

The simple to use “Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B” (REACH-B) scoring system

management of chronic hepatitis B infection – Diagnosis

Key words: chronic hepatitis B (慢性乙型肝炎), Diagnosis(診斷), Management (治理)

Dr lui Yan Ni (呂恩妮醫生)

Specialist in Gastroenterology and Hepatology

MBChB (CUHK), BMedSc (CUHK), MRCP (UK), FHKCP, FHKAM (Medicine)

table 1. Definitions of chronic hepatitis B infection, chronic active hepatitis B infection and inactive chronic hepatitis B carrier status2

Diagnostic criteria

chronic hepatitis B infection • HBsAg-positive for more than 6 months

chronic active hepatitis B infection

• HBsAg-positive for more than 6 months• Serum HBV DNA ≥20,000 IU/mL, but lower HBV DNA levels

(2,000–20,000 IU/mL) are often seen in HBeAg-negative chronic active hepatitis B

• Persistent or intermittent elevation in ALT/AST levels• Liver histology suggestive of chronic hepatitis with moderate

or severe necroinflammation

inactive chronic hepatitis B carrier

• HBsAg-positive for more than 6 months• HBeAg negative and anti-HBeAb positive• Serum HBV DNA <2000 IU/mL• Persistently normal ALT/AST levels• Liver histology confirms absence of significant hepatitis

HBsAg, hepatitis B surface antigen; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT/AST, aminotransferase/alanine aminotransferase ratio.


has been recently developed and val-idated.13 The score accurately estimated the risk of developing HCC at years 3, 5, and 10 in patients with chronic hepatitis B. The scoring system uses parameters including age (advanced age is associated with higher risk of HCC), gender (male patients had higher risk of HCC), HBeAg status (HBeAg positive is associated with higher risk of HCC), ALT level (higher ALT level is associated with higher risk of HCC), and viral load (higher viral load is associated with higher risk of HCC). Clinical decisions can be made based on the patient’s risk of developing HCC as as-sessed by the REACH-B scoring system.

Since the progression of liver diseases in chronic hepatitis B infection can lead to significant liver-related mor-bidities and mortalities, identification of patients who require antiviral therapy through monitoring is critical to improving clinical outcomes. Table 2 summarizes the current American Association for the Study of Liver Diseases (AASLD) recom-mendations on the monitoring of chronic hepatitis B patients.2 Parameters, in-cluding the presence of fibrosis/cirrhosis, viral load, HBeAg status, and ALT level, should be considered prior to reaching any clinical decision. Although liver biopsy remains the gold standard for assessing liver fibrosis/cirrhosis, recent devel-opments have focused on measuring liver stiffness using transient elastography (Fibroscan®, Echosens, Paris, France). Previous studies have demonstrated the

diagnostic value of liver stiffness mea-surement in patients with significant liver fibrosis, with good correlation to liver biopsy established for patients with peri-cellular fibrosis.14 As such, liver stiffness measurement can potentially provide clinicians with a simple, noninvasive mo-dality of liver fibrosis/cirrhosis monitoring in chronic hepatitis B infection, as well as a wide range of other liver diseases.14,15

Summary

Prevention of liver disease progression is the ultimate treatment goal for patients with chronic hepatitis infection. Man-agement of chronic hepatitis B infection patients should be guided by clinical pa-rameters, including the presence of liver fibrosis/cirrhosis, HBV viral load, HBeAg status, ALT level, as well as host factors such as age and gender. Specialist re-ferral should be considered for patients with active chronic hepatitis B infections to evaluation of the need for antiviral therapy.

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antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology 1987;92:1839-1843.

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etiology. J Hepatol 1990;10:29-34.7. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across

a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-67.

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table 2. management of chronic hepatitis B infection2

hBv Dna by PcR (iu/ml)

aLt histology management

hBeag-positive >20,000 ≤2 x *ULN - • Observe; consider treatment when ALT becomes elevated.• Consider biopsy in patients older than 40 years, ALT persistently high

normal to 2x ULN, or with family history of HCC.• Consider treatment if biopsy shows moderate/severe inflammation or

significant fibrosis.

>20,000 >2 x ULN - • Observe for 3–6 months and start treatment if no spontaneous HBeAg loss.• Consider liver biopsy before starting treatment if compensated.• Immediate treatment if clinical decompensation.

Detectable - Cirrhosis • Consider treatment

hBeag-negative >20,000 >2 x ULN - • Consider treatment

>2,000 1 to >2 x ULN - • Consider liver biopsy and start treatment if histology is suggestive of moderate/severe necroinflammation or significant fibrosis.

≤2,000 ≤ULN - • Observe, treat if HBV DNA or ALT elevates.

Detectable - Cirrhosis • Consider treatmentHBeAg, hepatitis B e antigen; ULN, upper limit of normal; ALT, aminotransferase; HCC, hepatocellular carcinoma; HBV DNA, hepatitis B virus deoxyribonucleic acid*Note: Recent studies suggest that the upper limits of normal for ALT and AST should be decreased to 30 U/L for men and 19 U/L for women16

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