vol. 3 - the society of physicians of hong kong · journal of july 2011 • vol. 3 • no. 4 the...

JULY 2011 • VoL. 3 • No. 4

Journal of the Society of PhySicianS of hong Kong

ISSN 2072-4209

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

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

• niacin for the treatment of Dyslipidaemia and atherosclerosis

DrMiaoHu,Teresa(胡淼博士);ProfessorBrianTomlinson(湯寧信教授)

• Use of Lasers in asians, Part 1: treatment of acquired Pigmentary Disorders

DrChiuLaiShan,Mona(趙麗珊);DrYeungChiKeung(楊志強醫生);DrChanHinLee,Henry(陳衍里醫生)

• Update on gastro-oesophageal Reflux Disease

DrWongChunYu,Benjamin(王振宇醫生)

CONTENTS

42 niacin for the treatment of Dyslipidaemia and atherosclerosis

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

46 Use of Lasers in asians, Part 1: treatment of acquired Pigmentary Disorders

Dr Chiu Lai Shan, Mona (趙麗珊); Dr Yeung Chi Keung (楊志強醫生); Dr Chan Hin Lee, Henry (陳衍里醫生)

49 corrections: May 2011, Vol. 3, no. 3

52 Update on gastro-oesophageal Reflux Disease Dr Wong Chun Yu, Benjamin (王振宇醫生)

Journal of the Society of PhySicianS of hong Kong

JULY 2011 • VoL. 3 • No. 4

www.sophysicianshk.org

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

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

HoN. TREaSuRER

Dr Lam how Mo, ignatius 林孝武醫生

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 Leung Wai Keung 梁偉強醫生

Dr Li Siu Lung, Steven 李少隆醫生

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

EditorialThe role of statins in the management of cardiovascular risk has become firmly established, and substantial reductions in low-density lipoprotein cholesterol can be achieved relatively easily with the more potent drugs in this group. This results in significant reductions in car-diovascular events and mortality. However, it is apparent that some degree of risk remains, and statins are not always effective in reducing triglyceride levels and have limited effects in increasing high-density lipoprotein cholesterol (HDL-C). Furthermore, some patients can only tolerate statins in small inadequate doses, and a few patients cannot tolerate them at all, so it is necessary to look for additional or alternative treatments which can correct the remaining lipid abnormalities and hopefully reduce the residual cardiovascular risk.

At present, the choice of drugs to reduce triglycerides and increase HDL-C lies mainly between fibrates and niacin. Niacin is an old drug which has not been used widely because of the troublesome side effect of flushing, but in recent years the newer intermediate-release formulations and the development of laropiprant, which can effectively inhibit the flushing reaction, have given a boost to the more widespread use of this medication.

The first article in this issue of the journal provides a brief review of the role of niacin in the management of dyslipidaemia and atherosclerosis.

Professor Brian Tomlinson湯寧信教授BSc, MBBS, MD, FRCP (Lond, Edin, Glasg), FACP, FHKCP, FCP, FHKAM (Med)

Specialist in Internal Medicine

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

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 Wong

T +852 2155 8557e-mail: [email protected]

© 2011 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.

LDL-C: –19%c HDL-C: 20%c TG: –25%d

n = 469Placebo-adjusted values

TREDAPTIVE® (ER Niacin/laropiprant, MSD) tablets is indicated for patients with combined dyslipidemia (type IIa and IIb according to Frederickson) and primary hypercholesterolemia (heterocygeous familial and non-familial), to reduce total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B) and triglycerides (TG) and increase high-density lipoprotein cholesterol (HDL-C) when not controlled by diet and exercise alone. TREDAPTIVE can be used in combination with HMG-CoA reductase inhibitors (statins) or as monotherapy.

Select Safety InformationTREDAPTIVE is contraindicated for use in patients with hypersensitivity to the active substances or to any of the excipients, significant or unexplained hepatic dysfunction, active peptic ulcer disease, or arterial bleeding.

TREDAPTIVE was generally well tolerated in clinical studies. The most common side effects is flushing. Other side effects seen in controlled clinical trials in ≥1% of patients included diarrhea, dyspepsia, nausea, vomiting, feeling hot, dizziness, headache, paresthesia, erythema, pruritus, rash and urticaria.

Liver function tests are recommended before initiation, every 6 to 12 weeks for the first year, and periodically (e.g., semiannually) thereafter. Should an increase in ALT or AST of ≥3X ULN persist, reduction of dose or withdrawal of TREDAPTIVE is recommended.

Physicians contemplating combined therapy with statins and TREDAPTIVE should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dosage of either drug is increased. Periodic serum CK should be considered in such situations.

Caution should be used when treating Chinese patients with TREDAPTIVE coadministered with simvastatin or ezetimibe/simvastatin (particularly simvastatin doses of 40 mg or higher). Because the risk of myopathy with statins is dose related, the use of TREDAPTIVE with simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with TREDAPTIVE coadministered with simvastatin or ezetimibe/ simvastatin.

Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycemic therapy may be necessary. TREDAPTIVE should be used with caution in patients with renal dysfunction, acute coronary syndrome, or with gout (or predisposed to gout). As with other niacin products, TREDAPTIVE was associated with small reductions in platelet count.

Please consult the full Prescribing Information before initiating therapy.

Data from a study of TREDAPTIVE 2 g/40 mg relative to placebo. The primary end point was safety and LDL-C percent change from baseline across weeks 12 to 24. Patients (N = 1,613; mean age: 58 years) were randomized to TREDAPTIVE 1 g/20 mg (n = 800), nicotinic acid 1 g (prolonged-release formulation) (n = 543), or placebo (n = 270) for 4 weeks; patients then advanced directly to TREDAPTIVE 2 g/40 mg, nicotinic acid 2 g, and placebo, respectively, for a total treatment duration of 24 weeks.1

a Each tablet of TREDAPTIVE contains 1 g of extended-release niacin and 20 mg of laropiprant, a novel flushing pathway inhibitor.2

b Patients received the following statins: atorvastatin (29%), simvastatin (54%), other statins (pravastatin, fluvastatin, rosuvastatin, lovastatin; 17%). Nine percent of statin patients were taking ezetimibe. Baseline values for the entire cohort were: LDL-C, 113.5 mg/dL (2.9 mmol/L) (mean); HDL-C, 50.8 mg/dL(1.3 mmol/L) (mean); and TG, 127.0 mg/dL (1.4 mmol/L) (median).1

c Mean percent change from statin-treated baseline.d Median percent change from statin-treated baseline.

References: 1. Maccubbin D, Bays HE, Olsson AG, et al. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2008;62:1959–1970. 2. Hong Kong Product Circular (TREDAPTIVE, MSD)

With risk coming from multiple directions, add on a multidimensional lipid therapy.

TREDAPTIVE® sends lipids in the right direction. Significant improvements with 2 g/40 mg when added to a statin (P < 0.001)1,a,b

Copyright © 2011 Merck & Co., Inc. All rights reserved. 06-2013-CVT-10-HK-1010-J (Reval 0) Multidimensional Lipid Therapy

(ER niacin/laropiprant, MSD) tabletsMerck Sharp & Dohme (Asia) Ltd.27/F., Caroline Centre, Lee Gardens Two, 28 Yun Ping Road, Causeway Bay, Hong Kong.Tel: (852) 3971 2800 Fax: (852) 2834 0756

Journal of The Society of Physicians of Hong Kong 42

Increased levels of low-density lipo-protein cholesterol (LDL-C) or apo-lipoprotein (apo) B and decreased levels of high-density lipoprotein cho-

lesterol (HDL-C) or apoAI are major risk factors for coronary heart disease (CHD).1 Lowering LDL-C with statins reduces cardiovascular disease (CVD) events, and greater reductions produce greater benefits.2 However, even with very low levels of LDL-C from intensive statin treatment, lower levels of HDL-C still in-crease the risk of CVD events and con-tribute to the residual CVD risk remaining during statin treatment.3

Nicotinic acid or niacin is the most potent HDL-C–raising agent among cur-rently available lipid-modifying therapies. It has been used for the treatment of a wide range of lipid disorders for over 50 years, and was the first lipid-modifying drug to show benefits in CVD events and mortality in the Coronary Drug Project (CDP).4,5 This article provides a brief overview of the pharmacological prop-erties, mechanism of action, and the tol-erability and efficacy of niacin in clinical settings.

Pharmacodynamic Profile

Niacin is one of the naturally occurring B vitamins (vitamin B3), and dietary de-ficiency results in pellagra. Pharmaco-logical doses have favourable effects on all traditionally measured lipid parameters, including increases in HDL-C and apoAI and decreases in atherogenic apoB-containing particles, LDL-C, triglycerides (TG) and lipoprotein (a) (Lp[a]).4-6 Niacin also improves HDL and LDL particle size, and is the only lipid-modifying drug with a beneficial effect on levels of Lp(a).7 Clinical studies have shown that niacin, alone or in combinations (mainly with statins), significantly reduces total mor-

niacin for the treatment of Dyslipidaemia and atherosclerosis

tality and coronary events and retards progression or induces regression of carotid or coronary atherosclerosis.4,5,8,9

Side Effects

The major adverse effect of niacin is the vasocutaneous flushing reaction, which occurs at doses producing significant lipid profile changes. This results from the release of prostaglandins, partic-ularly prostaglandin D2 (PGD2) and to a lesser extent PGE2, from subcutaneous Langerhans cells activated via the niacin receptor, a G protein-coupled receptor (GPR-109A).6 Aspirin and non-steroidal anti-inflammatory agents reduce the severity of niacin-related flushing by in-hibition of prostaglandin synthesis, al-though it remains controversial what the ideal dose of aspirin should be for this purpose.10,11 To reduce flushing, niacin should be started at low night-time doses (eg, 375 mg daily) and increased gradually at intervals of at least 1 week up to 2,000 mg daily if tolerated. Laropiprant has been developed as a selective blocking agent for the prostaglandin DP1 receptor which mediates the vasodilating effects of PGD2.12 The fixed dose combination of laropiprant 20 mg with niacin 1 g (Tre-daptive®, Merck Sharp & Dohme (Asia) Ltd.) allows initiation and rapid titration of high doses of niacin with minimal flushing.12

The safety profile of various dif-ferent formulations of niacin (immediate-release, intermediate-release referred to as extended- or prolonged-release, and slow-release niacin) appears to be largely dependent on how the drug is metab-olized through two major pathways.8,13 (Figure 1) One pathway has low affinity but high capacity forming nicotinuric acid by conjugating niacin with glycine, and this product is associated with flushing. The other pathway has high affinity but low capacity and leads to formation of

Key words: Niacin (煙酸), dyslipidaemia (血脂異常), atherosclerosis (動脈粥樣硬化)

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)


Head, Division of Clinical Pharmacology, Department of Medicine and Therapeutics, Chinese University of Hong Kong


43 Journal of The Society of Physicians of Hong Kong

several metabolites, some of which are associated with hepatotoxicity. Im-mediate-release formulations can rapidly saturate the high affinity pathway leading to greater conversion to nicotinuric acid, whereas slow-release formulations can delay drug absorption and thus in-crease the amount of drug metabolized by the high affinity pathway. The newer intermediate-release formulations such as Niaspan® (Abbott Laboratories Ltd.) and Tredaptive® were designed to achieve an optimal balance of metabolism between the two major pathways with minimal risk of liver toxicity.8

Treatment with niacin increases glucose levels to an unpredictable degree in some patients with diabetes or impaired glucose control. This can be managed by adjusting the diet and treatments for diabetes if necessary, and the benefits on lipids appear to outweigh any adverse effect on glycaemic control.14,15 Uric acid levels also tend to increase during treatment with niacin, and patients at high risk of gout attacks may require ad-justment of prophylactic treatment with allopurinol or other medications.15

Mechanism of Action

Although the exact mechanisms of action of niacin remain uncertain, the benefits appear to be mediated by favourable effects on TG and HDL metabolism. There is evidence that niacin decreases TG li-polysis in adipose tissue by inhibiting the hormone-sensitive lipase via the niacin

receptor GPR109A, thereby reducing the release of free fatty acids (FFAs). The de-creased flux of FFAs to the liver reduces TG synthesis and subsequent hepatic release of larger size TG-rich very low-density lipoprotein (VLDL) particles.7,8,12,16 (Figure 2) Niacin also appears to decrease TG- and apoB-containing lipoproteins in the liver by inhibiting hepatic diacylg-lycerol acyltransferase-2 (DGAT2), a key enzyme that catalyzes the final step of TG synthesis.17 (Figure 2) There is also good evidence indicating that niacin retards the hepatic catabolism of apoAI (as opposed to apoAII) by inhibiting the putative he-patocyte HDL catabolism receptor (β-chain adenosine triphosphate synthase), which explains the increase in half-life of HDL particles and in the concentrations of apoAI-containing HDL subfractions, and this augments reverse cholesterol transport.7,12 (Figure 2) Several in vitro studies have also described anti-inflam-matory properties of niacin in decreasing atherosclerosis, independent of its role as a lipid-modifying drug.7

Effect of Niacin on Lipoproteins

Niacin is the most efficacious agent currently available for increasing low HDL-C levels; it typically produces dose-dependent increases of 15% to 35%.8 Niacin reduces elevated TG levels by 15% to 40%, and higher doses reduce LDL-C by up to 25%. Furthermore, niacin can

reduce circulating concentrations of ath-erogenic Lp(a) by 30% or more in some patients in a dose-dependent manner,8 and this may be very important as current evidence suggests that elevated Lp(a) is causally related to premature CVD/CHD.18

Effect of Niacin on Atherosclerosis and Cardiovascular Risk

Several clinical studies have investigated the effect of niacin on atherosclerosis and CVD outcomes, and a recent meta-analysis of 11 randomized controlled trials involving 2,682 patients in the niacin groups and 3,934 in the control groups concluded that there were positive effects with niacin alone or in combi-nation therapy on all CVD events and on slowing carotid atherosclerosis pro-gression.9 (Table)

Niacin was first shown to have a fa-vourable impact on reducing CVD events in the CDP trial conducted between 1966 and 1975. In this prospective, placebo-controlled, double-blind study in 8,341 men with previous myocardial infarction (MI), niacin significantly reduced nonfatal recurrent MI by 26% but did not de-crease total mortality as compared with placebo over a total follow-up of 5 to 8.5 years.19 The subsequent 15-year follow-up of subjects enrolled in the study showed that mortality in the niacin group was 11% lower than in the placebo group

N

O

OH

N

O

NH2

N

O

NH2

O

N

O

O

NH2

N

NH

O

O

OH

Nicotinuric acid

Nicotinamide

Niacin

6HN NNO MNA

2PY 4PY

NAD

Pathway 1 Pathway 2

CH3 CH3

Niacin

Adipose tissue

GPR109A

Hormone-sensitive TG lipase

TG hydrolysis

FFA release

TG synthesis

Niacin

Niacin

DGAT2

HDL-catabolism receptor

SR-BI

HDL apoA-I uptake/removal

ApoA-I and reverse cholesterol transport

LiverLarge TG-rich VLDL1 Small dense LDL

VLDL, LDL

Assembly of apoB-containing lipoproteins

Intracellular apo B degradation

{

figure 1. Metabolism of niacin

Adapted from reference 8. 6HN = 6-hydroxynicotinamide; MNA = N-methylnicotinamide; NAD = nicotinamide adenine dinuleotide; NNO = nicotinamide-N-oxide; 2PY = N-methyl-2-pyridone-5-carboxamide; 4PY = N-methyl-4-pyridone-3-carboxamide.

N

O

OH

N

O

NH2

N

O

NH2

O

N

O

O

NH2

N

NH

O

O

OH

Nicotinuric acid

Nicotinamide

Niacin

6HN NNO MNA

2PY 4PY

NAD

Pathway 1 Pathway 2

CH3 CH3

Niacin

Adipose tissue

GPR109A

Hormone-sensitive TG lipase

TG hydrolysis

FFA release

TG synthesis

Niacin

Niacin

DGAT2

HDL-catabolism receptor

SR-BI

HDL apoA-I uptake/removal

ApoA-I and reverse cholesterol transport

LiverLarge TG-rich VLDL1 Small dense LDL

VLDL, LDL

Assembly of apoB-containing lipoproteins

Intracellular apo B degradation

{

figure 2. Proposed mechanism of action of niacin on lipoprotein metabolism

ApoA-I = apolipoprotein A-I; apoB = apolipoprotein B; DGAT2 = diacylglycerol acyltransferase-2; FFA = free fatty acid; GPR109A = G protein-coupled receptor 109A; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SR-BI = scavenger receptor class B type I; TG = triglyceride; VLDL = very low-density lipoprotein.Adapted from reference 12.


(52.0% vs 58.2%; p=0.0004), suggesting a late clinical benefit of niacin.20

In the Arterial Biology for the In-vestigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2) study, addition of extended-release (ER) niacin to ongoing statin therapy for 12 months in 167 patients with known CHD and low HDL-C substantially slowed the progression of carotid intima-media thickness (CIMT) by 68% vs placebo, with CIMT remaining unchanged relative to baseline levels in the ER niacin group.21 Furthermore, in a follow-up of ARBITER-2 (ARBITER-3), 57 patients receiving ER niacin for 24 months showed additional significant regression of CIMT (-0.041 ± 0.021 mm; p=0.001 vs placebo).22 The recent ARBITER 6: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6–HALTS) study has shown that in patients with CHD or a CHD risk equivalent who were receiving long-term statin therapy, and with LDL-C <2.6 mmol/L and HDL-C <1.3 or 1.4 mmol/L (for males and females, respectively), niacin resulted in significant regression of CIMT and was superior to ezetimibe after 8 and 14 months of treatment. The in-cidence of major CVD events was low in both groups, but was lower in the niacin group than in the ezetimibe group (1% vs 5%; p=0.04).23

Although niacin has demonstrated beneficial effects on CV outcomes and

atherosclerosis evolution in clinical trails, most of these endpoint trials only in-volved small numbers of patients and had few CVD events with relatively short follow-up periods, and the maximum doses of niacin used in some early studies were higher than those currently recom-mended.8,9 (Table) Two large prospective trials, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High TG: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), were initiated to evaluate the effect of niacin on CVD outcomes, hoping to answer the question on whether the addition of niacin to statin decreases CVD events conclusively.

AIM-HIGH Stopped PrematurelyThe AIM-HIGH trial was stopped pre-maturely by the US National Heart Lung and Blood Institute (NHLBI) in May 2011 as the addition of high-dose extended-release (ER) niacin to simvastatin was not found to reduce the primary endpoint of composite cardiovascular events at 32-month follow-up, and was associated with a slight increase in ischaemic stroke (1.6% vs 0.7%).30 Some of the subjects in the niacin group who had stroke had already stopped niacin treatment for several months and up to 4 years.

The trial enrolled patients with stable established atherosclerotic CVD who had low HDL-C and high TG. Par-ticipants were randomized to either ER niacin (Niaspan®) in gradually increasing doses of up to 2,000 mg per day (n=1,718) or placebo (n=1,696). LDL-C levels were maintained in the target range of 40–80 mg/dL (1.0–2.1 mmol/L) with simvastatin and additional ezetimibe when necessary. The average expected increases in HDL-C and reduction of TG levels were seen in participants taking niacin compared to those on statin alone. It will be interesting to see if any subgroups of patients ben-efited from niacin treatment in the sub-sequent, more detailed analysis. In our experience, there is considerable inter-individual variation in lipid responses to niacin, which may be related to a combi-nation of genetic and phenotypic factors, and it seems likely that the personalized medicine approach with careful selection of patients having the most appropriate baseline phenotype and those who show the most satisfactory response to niacin treatment should have advantages. The HPS2-THRIVE study is larger and in-cludes a wider range of patients, and should help to answer some of the outstanding questions.

table. Summary of major niacin trials reporting cardiovascular events with a follow-up period ≥1 yeartrial active group control group follow-up (years) cV events in

active group (n/n)cV events in

control group (n/n)odds ratio (95%ci)

ARBITER 6–HALTS (2009)23

Niacin 2 g + any statin

Ezetimibe 10 mg + any statin

1.2 2/187 9/176 0.25 (0.08, 0.84)

AFREGS (2005)24 Niacin 0.25–3 g + gemfibrozil 1.2 g + cholestyramine 2 g

Placebo 2.5 1/71 2/72 0.52 (0.05, 5.04)

ARBITER-2 (2004)21 Niacin 0.5–1 g + any statin

Placebo + any statin 1 3/87 7/80 0.39 (0.11, 1.40)

HATS (2001)25 Niacin 1–4 g + simv-astatin 10–20 mg

Placebo 3 1/38 12/38 0.13 (0.04, 0.44)

UCSF_SCOR (1990)26 Niacin 0–7.5 g + colestipol 15–20 g

Usual care 2.2 0/48 1/49 0.14 (0.00, 6.96)

FATS (1990)27 Niacin 4 g + colestipol 30 g

Usual care 2.7 2/48 10/52 0.24 (0.07, 0.81)

STOCKHOLM (1988)28 Niacin 3 g + clofibrate 2 g

Usual care 5 73/279 104/276 0.59 (0.41, 0.84)

CLAS (1987)29 Niacin 4 g + colestipol 30 g

Placebo 2 17/94 21/94 0.77 (0.38, 1.56)

CPD (1975)20 Niacin 3 g Placebo 6.2 914/1,119 2,333/2,789 0.87 (0.72, 1.05)

Adapted from reference 9.

A complete list of references can be downloaded from

www.SOPHYSICIANSHK.org


Background

There is an increasing demand of cosmetic laser procedures from the expanding Asian population. Understanding the racial dif-

ferences in tissue response to laser and light-based therapy is essential to achieve optimal outcomes and minimize compli-cations.1 The risk of postinflammatory hyperpigmentation (PIH), blistering and subsequent scarring is higher in Asians following laser therapy that induces skin inflammation. Photoageing in Asian skin (Fitzpatrick skin types III–V) often manifests at a later age as lentigines in females and seborrhoeic keratosis in males, in contrast to the early onset of deep wrinkles in Caucasians.2 Dermal pig-mented lesions, including nevus of Ota and bilateral nevus of Ota-like macules (ABNOMS, Hori’s macules), are more commonly seen in Asians.

Laser application on Asian skin differs from that on Caucasian skin in several aspects. While the densities of melanocytes in Asians and Caucasians are similar, more and larger melanosomes are present in Asian skin than white skin.3 The higher epidermal melanin content in Asian patients may affect the efficacy of lasers in treating dermal lesions, as melanin has a wide absorption spectrum (from ultraviolet to near-infrared range) and thus competes for the laser energy. PIH is more commonly seen as an adverse effect after laser therapy in Asians because the epidermal melanin absorbs laser energy, resulting in epi-dermal damage as well as reduced ex-posure of target skin components. Caution needs to be exercised when lasers are used in Asian skin in view of reduced effectiveness and higher compli-cation rate.

Clinical applications of laser and light sources in Asian skin comprise treatments for pigmented lesions, vascular birthmarks, laser hair removal,

skin rejuvenation and acne scarring. Part 1 of this review discusses the use of lasers and pulsed light devices for treatment of acquired pigmentary conditions in Asians. In part 2 of the series to be published later in this year, treatment of other con-ditions including acne scarring and port wine stain will be addressed.

Lasers for Pigmentary Disorders

Pigmentary disorders such as lentigines, melasma, seborrhoeic keratosis, nevus of Ota and Hori’s macules are more common in Asians than in Caucasians. In addition, there are differences in epi-dermal melanin content and features of photoageing as mentioned above. As melanin acts as a competing chro-mophore, a higher fluence is usually necessary for the light source to reach the target tissue. As a result, the pre-vention of PIH is the major challenge in treatment of Asian skin, particularly in the hands of clinicians who are less familiar with dark-skinned patients.

Freckles and LentiginesQ-switched (QS) lasers such as QS neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, QS ruby, and QS alexandrite lasers are the most effective treatments for freckles and lentigines in fair-skinned patients. However, there is a high risk of PIH of around 25% among Asian patients.4-6 Studies have shown that long-pulsed pigment laser has similar ef-ficacy but a lower risk of PIH vs QS device in treating lentigines in Asians.6 It is sug-gested that QS device, which generates high energy (1,000,000 W/cm2) within nanoseconds, produces photothermal as well as photomechanical effects. The later can induce damage in surrounding oxyhaemoglobulin and melanin, resulting in inflammation of surrounding vessels

Use of Lasers in asians, Part 1: treatment of acquired Pigmentary Disorders

Dr Chiu Lai Shan, Mona (趙麗珊)MBChB (CUHK), MRCP (UK), FHKCP, FHKAM (Med)

Specialist in Dermatology

Dr Yeung Chi Keung (楊志強醫生)MBBS, MRCP(UK), FRCP(Edin), FHKCP, FHKAM(Medicine)

Associate Consultant & Honorary Clinical Assistant Professor, Division of Dermatology, Department of Medicine, University of Hong Kong

Dr Chan Hin Lee, Henry (陳衍里醫生)MD, PhD, FRCP (London, Edinburgh, Glasgow), FHKCP, FHKAM (Medicine)

Specialist in Dermatology

Honorary Professor, Li Ka Shing Faculty of Medicine, University of Hong Kong

Visiting Scientist, Wellman Center for Photomedicine, Harvard Medical School, Boston, USA

Key words: Laser (激光), asian (亞洲人), pigment (色素)


and alteration of melanocyte activity, thereby causing subsequent PIH.7

To reduce the risk of purpura and PIH, the technique of compression window to empty blood vessels has been proposed.8 Hemosiderin deposition, re-sulting from purpura, contributes to the appearance of PIH. Kono et al conducted a study using 595 nm long-pulsed dye laser with a glass window attached to the tip for compression of skin (fluences between 9–13 J/cm2 and a constant pulse duration of 1.5 ms) for treatment of len-tigines in Asians.8 The intention was to compress and empty blood vessels to remove haemoglobin as a competing chromophore. Excellent response was noted in 70% of patients. PIH was only found in one out of 54 patients. Another study, also by Kono et al, compared the efficacy and safety of 694 nm QS ruby laser (spot size 4 mm, fluence 6–7 J/cm2, pulse duration 30 ns) and 595 nm long-pulsed dye laser (spot size 7 mm, fluence 10–13 J/cm2, pulse duration 1.5 ms) de-livered with compression in treatment of facial lentigines in 18 Asian patients.9 The degree of clearance was higher with long-pulsed dye laser (83.3%) than ruby laser (70.3%), but no PIH was found in the former group. The use of a small spot size device is another way to achieve the greatest degree of improvement with the least complication. A retrospective study in Hong Kong by Ho SG et al compared the treatment result of freckles and len-tigines with four difference devices, namely 595 nm long-pulsed dye laser, 755 nm long-pulsed dye alexandrite laser, 532

nm QS Nd:YAG laser and 532 nm long-pulsed Nd-YAG laser.10 The 532 nm long-pulsed Nd-YAG laser with a compression window achieved the greatest effect with the least complication. (Figure 1)

For patients who expect minimal downtime and lower risk of PIH, intense pulsed light (IPL) system is a good option. However, multiple sessions are needed for clinical improvement. Several studies have demonstrated the effectiveness in treatment of epidermal pigmentation in Asian patients. In a study by Negishi et al that evaluated the effectiveness of IPL in photorejuvenation in Asian patients (n=97), >90% reported a reduction in pig-mentation after three to six treatments at intervals of 3–4 weeks (cut-off filter 550 nm, 28–32 J/cm2, double-pulse mode of 2.5–4.0/4.0–5.0 msec, delay time 20.0/40.0 msec).11 Another study (n=73), also by Negishi et al, showed that 80% of Asian patients had significant reduction in pigmentation after three to five treatments with IPL with inte-grated cooling system (cut-off filter 560 nm, 23–27 J/cm2, double-pulse mode of 2.8–3.2/6.0 msec, delay time 20.0/40.0 msec), delivered at intervals of 3–4 weeks.12 Kawada et al reported that 68% of patients (total n=60) had >50% im-provement when using IPL (cut-off filter 560 nm, 20–24 J/cm2, 2.6–5.0 msec pulse duration in double or triple pulses, delay time 20 sec, three to five treatments at intervals of 2–3 weeks) to treat freckles and lentigines.13 The most important common finding of these studies was the low risk of PIH. In the authors’ expe-

rience, if the contrast between lesional and nonlesional skin is small, then IPL does carry a risk given its large spot size. (Figures 2 and 3) However, if the contrast is large, IPL does represent an alternative treatment modality as other features of photoageing can also be improved. As IPL is less selective given its broad spectrum characteristic, more treatment sessions are required to achieve the de-sirable clinical outcome.

In essence, long-pulsed pigment lasers with a compression window and a small spot size should be the best choice for treatment of freckles and lentigines in Asian patients, as they offer high efficacy and a very low risk of PIH. QS lasers are more effective and require fewer treatment sessions, but do carry a higher risk of PIH.

MelasmaTreatment of melasma is challenging. In melasma skin, there is an increased number of melanocytes with widely dis-persed melanosomes. The increased ac-tivity of melanogenic enzymes results in hyperactive melanocytes with increased synthesis and transfer of melanosomes, and decreased degradation of mela-nosomes in keratinocytes. Sublethal laser damage to these labile melanocytes can increase the production of melanin and lead to PIH.14 The use of QS ruby laser and 510 nm pigmented lesion dye laser may lead to worsening of pigmentation, while IPL can lead to manifestation of previously subclinical melasma in some cases.15-18

Ablative lasers such as carbon dioxide lasers and QS alexandrite lasers have been used for treatment of melasma.19-21 However, they are asso-ciated with significant downtime and adverse effects. To overcome these un-desirable effects, fractional skin resur-facing has been developed. This involves the creation of microscopic zones of thermal injury that spare the surrounding skin. Migration of keratinocytes from normal surrounding skin to the zone of thermal injury occurs, leading to rapid re-epithelialization of the damaged epi-dermis.22 Rokhsar and Fitzpatrick con-ducted a pilot study treating 10 female patients (Fitzpatrick skin types III–V) with melasma with 1,550 nm fractional

figure 1. treatment of freckles / lentigines using long-pulsed nd-yag laser with a compression window

After one LP532 treatmentBaseline


laser at 1- to 2-week intervals for four to six times.23 They used 6–12 mJ per microthermal treatment zone (MTZ) and 2,000–3,500 MTZ/cm2. A 75% to 100% clearing was reported in 60% of patients at 3 months. PIH was only found in one patient. Goldberg et al studied the his-tologic and ultrastructural changes of melasma in patients with skin types III–IV after treatment with fractional laser.24

They found a decrease in melanocytes and a relative absence of melanin in the surrounding keratinocytes in post-treatment specimens obtained 3 months after the final treatment, vs pretreatment specimens. This finding provides basic scientific evidence of the usefulness of fractional lasers in treatment of melasma. In the authors’ experience, given the fact that about 10% of patients develop gen-eralized PIH and there is no means to predict such outcome, fractional resur-facing should be used as an adjunctive therapy if topical treatment failed, and only if informed consent regarding the potential risk is obtained.

IPL has been studied for treatment of melasma in Asian patients. While tra-ditional IPL did not show very promising results in a study by Wang et al in Taipei, a new IPL (Lumenis One, Lumenis Co., Santa Clara, CA) with a uniform pulse profile had demonstrated significant clinical improvement with minimal adverse effects.18,25 In this study by Li et al in Beijing, 69 of 89 patients (77.5%) ob-tained 51% to 100% improvement, with the mean melasma area and severity index (MASI) score decreasing substan-tially from 15.2 to 4.5. Adverse effects were minimal. PIH was only found in three patients. The hypothesis is that traditional IPL sources have the short-coming of producing a “V-shaped” energy peak of pulses that can possibly cause overload burning and PIH. The energy slope below the therapeutic threshold is insufficient to produce photothermolysis on the targeted chromophores. Another hypothesis is that a flat-beam IPL system may result in safer, more effective, and more reproducible treatments. However,

factors other than the uniform profile of IPL may also account for the success of this study. Firstly, Beijing is situated in the northern part of China, where ul-traviolet light exposure is expected to be much lower than in places such as Hong Kong, Singapore, or California. Secondly, some of the subjects of this study had been treated with traditional Chinese medicine for which the effect on melasma was not well studied. Similar to fractional resurfacing, the efficacy of IPL is not too impressive with about 10% risk of deterioration and, therefore, its role is in second-line treatment as an adjunctive therapy.

Laser toning involves the use of large spot size, low fluence (8 mm, 3.1 J/cm2) QS 1,064 nm Nd:YAG lasers to induce mild erythema after repeated passes. This approach has been found effective in the treatment of melasma. However, frequent weekly treatments are necessary, and mottled hypopigmen-tation and recurrence of melasma have been reported.27

In summary, laser or IPL light source should still be considered an adjunctive or second-line therapy to topical bleaching agents for treatment of melasma in view of the conflicting data. Extra caution is required due to the nature of the disease, in which the hyperactive, labile melanocytes can be easily stimulated by sublethal light source resulting in hyperpigmentation.

Acquired Bilateral Nevus of ota-like Macules or Hori’s Macules

Acquired bilateral nevus of Ota-like macules (ABNOM) or Hori’s macules are a common pigmentary condition in Asians, with a prevalence of around 0.8%.23 QS ruby, QS alexandrite, and QS 1,064 nm Nd:YAG lasers have been shown effective in the treatment of Hori’s macules.28,29 Shorter treatment intervals and more treatment sessions appear to be necessary for a good result. Transient postoperative hyperpigmentation is a common adverse event, occurring in the majority of treated subjects.28,29

Permanent hypopigmentation has been reported after treatment with a QS ruby laser.27

figure 2. Pih after iPL treatment

PIH post IPL treatmentBaseline

figure 3. after two iPL treatments

After the second IPL treatmentBaseline


Combination treatment is a recent trend, as ABNOM often coexists with other pigmentary disorders such as melasma, lentigines, ephelides and seb-orrhoeic keratosis. Park et al has proposed the term “complex dyspigmentation” to describe this condition.30 Combination treatments can lead to more effective eradication of dermal pigmentation by synergistically eliminating epidermal pig-mentation; this allows more dermal pen-etration, leading to a possibly lower risk of PIH and a reduction in the number of treatment sessions.31 Studies using QS 532 nm Nd:YAG laser followed by a QS 1,064 nm Nd:YAG laser, QS ruby laser with topical bleaching treatment, and scanned carbon dioxide laser followed by QS ruby laser and QS alexandrite laser have shown promising results in the treatment of ABNOM.30-33

In the authors’ experience, patients should be warned prior to treatment that while ABNOM can resolve following laser therapy, it inevitably darkens after the first and second treatment sessions. At least four to six treatment sessions are often required at intervals of 4–6 weeks, with hypopigmentation being the most common complication in the long run.

Conclusion

Features of photoageing in Asians are different from those in Caucasians, with pigmentary problems being more common in the former. Laser treatment

on Asian skin can be performed ef-fectively and safely, provided that pre-cautions have been taken on selection of devices (based on skin type and patient expectations) and treatment pa-rameters to minimize epidermal injury and dyspigmentation. Adequate patient assessment and counselling about the risks of laser treatment is necessary, par-ticularly on the downtime and skin dys-pigmentation. Lower fluences and more treatment sessions as a conservative approach should be adopted in treating Asian skin.

References:1. Berardesca E, Maibach H. Ethnic skin: Overview of structure and

function. J Am Acad Dermatol 2003;48(6 Suppl):S139-S142.2. Chung JH. Photoaging in Asians. Photodermatol Photoimmunol

Photomed 2003;19:109-121.3. Alaluf S, Atkins D, Barrett K, Blount M, Carter N, Heath A. Ethnic

variation in melanin content and composition in photoexposed and pho-toprotected human skin. Pigment Cell Res 2002;15:112-118.

4. Wang CC, Sue YM, Yang CH, Chen CK. A comparison of Q-switched alexandrite laser and intense pulsed light for the treatment of freckles and lentigines in Asian persons: A randomised, physician-blinded, split- face comparative trial. J Am Acad Dermatol 2006;54;804-810.

5. Murphy MJ, Huang MY. Q-switched ruby laser treatment of benign pigmented lesions in Chinese skin. Am Acad Med Singapore 1994;23;60-66.

6. Chan HH, Fung WKK, Ying SY, Kono T. An in vivo trial comparing the use of different types of 532 nm Nd;YAG lasers in the treatment of facial lentigines in oriental patients. Dermatol Surg 2000;26;743-749.

7. Ara G, Anderson RR, Mandel KG, Ottesen M, Oseroff AR. Irradiation of pigmented melanoma cells with high intensity pulsed radiation generates acoustic waves and kill cells. Lasers Surg Med 1990; 10:52-59.

8. Kono T, Chan HH, Groff WF, et al. Long-pulse pulsed dye laser delivered with compression for treatment of facial lentigines. Dermatol Surg 2007;33:945-950.

9. Kono T, Manstein D, Chan HH, Nozaki M, Anderson RR. Q-switched ruby versus long-pulsed dye laser delivered with compression for treatment of facial lentigines in Asians. Lasers Surg Med 2006;38:94-97.

10. Ho SG, Chan HH, Chan NP, Yeung CK, Shek SY, Knon T. A retrospective comparative analysis of the management of freckles and lentigines using 595nm long pulsed dye laser, 755nm long pulsed alexandrite laser, 532 QS Nd:YAG laser and long pulsed 532nm Nd:YAG laser in oriental patients. Lasers Surg Med 2010;S22;136.

11. Negishi K, Tezuka Y, Kushikata N, Wakamatsu S. Photorejuvenation for Asian skin by intense pulsed light. Dermatol Surg 2001;27;627-632.

12. Negishi K, Wakamatsu S, Kushikata N, Tezuka Y, Kotani Y, Shiba K. Full-face photorejuvenation of photodamaged skin by intense pulsed light with integrated contact cooling: Initial experiences in Asian patients. Lasers Surg Med 2002;30:298-305.

13. Kawada A, Shiraishi H, Asai M, et al. Clinical improvement of solar len-tigines and ephelides with an intense pulsed light source. Dermatol Surg 2002;28:504-508.

14. Kang WH, Yoon KH, Lee ES, et al. Melasma: Histopathological character-istics in 56 Korean patients. Br J Dermatol 2002;146:228-237.

15. Grekin RC. Shelton RM, Geisse JK, Frieden I. 5l0nm pigmented lesion dye laser: Its characteristics and clinical uses. J Dermatol Surg Oncol 1993;19:380-387.

16. Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and post-inflammatory hyperpigmentation by Q-switched ruby laser. J Dermatol Surg Oncol 1994;20:592-597.

17. Negishi K, Kushikata N, Tezuka Y, Takeuchi K, Miyamoto E, Wakamatsu S. Study of the incidence and nature of “very subtle epidermal melasma“ in relation to intense pulsed light treatment. Dermatol Surg 2004;30:881-886.

18. Wang CC, Hui CY, Sue YM, Wong WR, Hong HS. Intense pulsed light for the treatment of refractory melasma in Asian patients. Dermatol Surg 2004;30:1196-1200.

19. Manaloto RM, Alster T. Erbiumi YAG laser resurfacing for refractory melasma. Dermatol Surg 1999;25:121-123.

20. Angsuwarangsee S, Polnikorn N. Combined ultrapulse C02 laser and Q-switched alexandrite laser compared with Q-switched alexandrite laser alone for refractory melasma: Splilt-face design. Dermatol Surg 2003;29:59-64.

21. Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J. Combination treatment of melasma with pulsed C02 laser followed by Q-switched alexandrite laser: A pilot study. Dermatol Surg 1999;25:494-497.

22. Chan HHL. Effective and safe use of lasers, light sources, and radio-frequency devices in the clinical management of Asian patients with selected dermatoses. Lasers Surg Med 2005;37:179-185.

23. Rokhsar CK, Fitzpatrick. The treatment of melasma with fractional photo-thermolysis: A pilot study. Dermatol Surg 2005;31:1645-1650.

24. Goldberg DJ, Berlin AL, Phelps R. Histologic and ultrastructural analysis of melasma after fractional resurfacing. Lasers Surg Med 2008;40:134-138.

25. Li YH, Chen JZ, Wei HC, et al. Efficacy and safety of intense pulsed light in treatment of melasma in Chinese patients. Dermatol Surg 2008;34:693-700.

26. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol 1984;10;961-964.

27. Wattanakrai P, Mornchan R, Eimpunth S. Low-fluence Q-switched neodymium-doped yttrium aluminum garnet (1,064 nm) laser for the treatment of facial melasma in Asians. Dermatol Surg 2010;36:76-87.

28. Lam AY, Wong DS, Lam LK, Ho WS, Chan HH. A retrospective study on the efficacy and complications of Q-switched alexandrite laser in the treatment of acquired bilateral nevus of Ota-like macules. Dematol Surg 2001;27:937-941.

29. Polnikon N, Tanrattanakom S, Goldberg DJ. Treatment of Hori’s nevus with the Q-switched Nd:YAG laser. Dermatol Surg 2000;26;477-480.

30. Park JM, Tsao H, Tsao S. Combined use of intense pulsed light and Q-switched ruby laser for complex dyspigmentation among Asian patients. Lasers Surg Med 2008;40:128-133.

31. Park JM, Tsao H, Tsao S. Acquired bilateral nevus of Ota-like macules (Hori’s nevus): Etiologic and therapeutic considerations. J Am Acad Dermatol 2009;61:88-93.

32. Ee HL, Goh CL, Khoo LS, Chan ES, Ang P. Treatment of acquired bilateral nevus of Ota-iike macules (Hori’s nevus) with a combination of the 532 nm Q-switched Nd:YAG followed by the 1064 nm Q-switched Nd:YAG is more effective: Prospective study. Dermatol Surg 2006;32:34-40.

33. Manuskiatti W, Sivayathorn A, Leelaudomlipi P, Fitzpatrick RE. Treatment of acquired bilateral nevus of Ota-like macules (Hori’s nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser. J Am Acad Dermatol 2003;48:584-591.

Corrections

Journal of the Society of Physicians of Hong Kong May 2011, Vol. 3, No. 3

In the article Atypical Femoral Fractures and Bisphosphonates: New Aspects by Dr. Kung Wai Chee, Annie, on page 34:

• The review by Giusti et al, described in the 3rd paragraph, should have been from reference 1.

• The report by the Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoar-thritis and the International Osteoporosis Foundation, described in the 4th paragraph, should have been from reference 5.


Introduction

although gastro-oesophageal reflux disease (GERD) is rela-tively common in the West, its prevalence in Asian countries

remains low, varying between 2% to 7%.1 However, there seems to be an increasing prevalence over most Asian countries. This article will discuss the diagnosis and management of typical and atypical GERD.

Definition

The definition of GERD remains contro-versial. According to the latest Montreal definition, it is a disorder that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.2 (Figure 1) Essentially,

GERD is a patient-driven diagnosis. Normal healthy persons have up to 40 reflux episodes over a 24-hour period.3 These reflux episodes are either not noticed by the persons or not causing troublesome symptoms, so they will not present to a doctor.

Presentation

There are two subgroups of GERD. One is the oesophageal syndrome and the other is the extra-oesophageal syndrome. Patients with oesophageal involvement present with acid regurgitation, heartburn, chest pain, acid in stomach, and dysphagia, etc.4 In Hong Kong, acid regurgitation is the most common presentation in GERD patients, while heartburn is present in <40%. This may be related to the lack of Chinese trans-lation of the symptom ‘heartburn’, so pa-tients may not describe their symptoms to doctors using this specific term. The oesophagus can have mucosal lesions including erosive oesophagitis, ulcers, strictures, Barrett’s oesophagus and ad-

enocarcinoma. However, >60% of GERD patients have no oesophageal mucosal lesions, and are sometimes classified as having nonerosive reflux disease (NERD). In addition, Barrett’s oesophagus and ad-enocarcinoma are rare entities in Hong Kong.5

The other group of patients may have extra-oesophageal manifestations of GERD, such as reflux cough syndrome, reflux asthma syndrome, reflux lar-yngitis syndrome or reflux dental erosion syndrome. A patient can have either or both oesophageal and extra-oesophageal symptoms. Idiopathic pulmonary fibrosis, pharyngitis, sinusitis and recurrent otitis media have been suggested as extra- oesophageal manifestations, but it remains controversial. Patients with laryngo-pharyngeal reflux (LPR) may present with hoarseness of voice, ody-nophagia, globus sensation, and frequent clearing of throat.

Patients in the NERD group consist of a heterogeneous population. It can be a patient with typical acid reflux shown on 24-hour pH tracing without visible oesophageal mucosal injury, or a patient

Update on gastro-oesophageal Reflux Disease

Key words: Gastro-oesophageal reflux disease (GERD) (胃食道反流症), proton pump inhibitor (質子泵抑製劑)

Dr Wong Chun Yu, Benjamin (王振宇醫生)

MBBS (HK), MD (HKU), PhD (HKU), MRCP (UK), FHKCP, FHKAM (Medicine), FRCP (Lond), FRCP (Glasg), FRCP (Edin).

Specialist in Gastroenterology and Hepatology

Honorary Clinical Professor, Department of Medicine, University of Hong Kong

figure 1. Montreal definition of geRD


geRD is a condition which develops when the reflux of gastric content causes troublesome symptoms or complications

oesophageal syndromes

extra-oesophageal syndromes

Symptomatic syndromes:1. Typical reflux syndrome2. Reflux chest pain syndrome

Syndromes with oesophageal injury:1. Reflux oesophagitis2. Reflux stricture3. Barrett’s oesophagus4. Oesophageal adenocarcinoma

established associations:1. Reflux cough syndrome2. Reflux laryngitis syndrome3. Reflux asthma syndrome4. Reflux dental erosion syndrome

Proposed associations:1. Pharyngitis2. Sinusitis3. Idiopathic pulmonary fibrosis4. Recurrent otitis media


with oesophageal hypersensitivity and normal 24-hour oesophageal pH. There is a drop of pH gradient from 7 to a value still above 4 when the patient experiences reflux symptoms. In this case, the strict criteria of reflux based on pH <4 in the 24-hour pH monitoring is not met.

The last group of patients is named having functional heartburn. They have normal 24-hour oesophageal pH, and the reflux symptoms do not correlate with any drop of pH gradient in the 24-hour oesophageal pH monitoring.

oesophageal Injury

The acid reflux leads to mucosal damage around the squamo-columnar junction. Reflux oesophagitis can be classified ac-cording to the latest Los Angeles classi-fication, with grade A being the mildest and grade D being the most severe. Oe-sophageal ulcers may lead to bleeding and stricture formation after healing. Bar-rett’s oesophagus represents upward migration of the gastric columnar epi-thelium, replacing part of the oesophageal squamous epithelium. This so-called ‘tongue’ of epithelium may sometimes be termed short-segment or long-segment Barrett’s oesophagus, depending on the longitudinal length of the ‘tongue’. The definition for diagnosis of Barrett’s oe-sophagus is still controversial, and some definitions require biopsy-proven presence of gastric intestinal metaplasia. Since Bar-rett’s oesophagus is a premalignant con-dition associated with increased risk of oesophageal adenocarcinoma, revealing the diagnosis to patients has a far-reaching impact, including medico-legal as well as insurance implications. Careful evaluation is necessary before we label the diagnosis to the patient. In that sense, some would suggest using the term “columnar lined epithelium” to report what we see during upper endoscopy while waiting for the biopsy result, in order not to overdiagnose the condition.

Diagnosis

The diagnosis of GERD involves any one or more of the following four methods. We have invented a seven-item questionnaire

in Cantonese.6 (Figure 2) Patients with a score ≥12 are likely suffering from GERD. The questionnaire is simple to use and accurate. However, it can only diagnose those with typical GERD symptoms, but not those with extra-oesophageal manifestations alone.

The second method is a proton pump inhibitor (PPI) test. Patients are pre-scribed 1–4 weeks of PPI. If symptoms improve, the patient is likely to suffer from GERD. Our meta-analysis showed that the PPI test is an accurate diagnostic tool, but the exact duration and optimal dose of PPI remains to be determined.7

The third method is upper en-doscopy to detect oesophageal mucosal lesions. However, as mentioned above, >60% of GERD patients do not have de-tectable oesophageal lesions on upper endoscopy. Hence, this method can only diagnosis patients with mucosal lesions.

The last method is ambulatory 24-hour oesophageal pH monitoring. A catheter with pH sensor is passed through the nose down to the oesophagus and stomach, and kept for 24 hours. The oe-sophageal sensor is placed at a point about 5 cm above the lower oesophageal sphincter (LES). Normally, the pH at this point is around 7. An episode of acidic reflux to this point will bring the pH to <7,

typically <4. Hence, if the pH value is <4 for more than 4.2% of the 24-hour period, the patient is likely having GERD. Patients are also asked to report the presence of heartburn, acid regurgitation or chest pain by pressing on preset buttons on the machine. The presence of symptoms will be matched with the pH tracings. The presence of symptoms together with a pH drop to <4 on the tracing indicates a positive symptom correlation. The presence of symptoms can also be asso-ciated with a pH drop, but to a value still above 4. This may happen in patients with oesophageal hypersensitivity, and still in-dicates a positive symptom correlation. However, in some patients, the presence of symptoms occur independent of any pH changes, and there is a negative symptom correlation. These patients suffer from functional heartburn and respond poorly to conventional treatment.

Ambulatory 24-hour oesophageal pH monitoring is usually regarded as the gold standard of diagnosing GERD. However, it is not widely available, is very uncomfortable, and is not very ac-curate. Recently, a catheter-free device called BRAVO has become available. It can be pinned to the lower oesophageal mucosa, detect the pH and send the data via radiofrequency transmission. The data

figure 2. cantonese geRD questionnaire



are captured by a receiver carried over the belt. The recording time is extended to 48 hours to increase the sensitivity. However, there are also adverse events including nasal bleeding during deployment of the device, or chest pain that may lead to immediate retrieval of the device.

Treatment

Treatment of GERD should provide quick symptom relief, heal oesophageal lesions (if any), and prevent long-term oesophageal complications. Lifestyle modification, drug therapy, surgery and endoscopic intervention are the mainstays of treatment.

Lifestyle modification includes weight reduction, exercise, elevation of the head of bed, etc. Risk factors, including consumption of alcohol, caffeinated drinks (eg, coffee or strong tea), or fruits with high acidity (eg, lemon), should be stopped. Night-time snacks should be avoided and no meal should be taken within 3–4 hours of bedtime. Overeating and carbonated drinks should be avoided. Unfortunately, lifestyle modification alone is only useful for very mild cases.

Drug therapy is necessary for most of the patients. A top-down approach is now recommended, starting with the most potent drug (ie, PPI). After complete control of symptoms, therapy can be stepped down to H2 blockers, prokinetics or antacids. This approach is the most ef-fective and most cost-effective option. PPI should be started at the recommended once-daily dose. For PPIs that need to be taken before meal, it is best given 30 minutes before breakfast for the once-daily dosing regime, and 30 minutes before breakfast and dinner for the twice-daily dosing regime. Some PPIs do not need to be given in relation to the timing of meal. A recent study showed that the 24-hour pH profile varies a lot, depending on the time of administration of PPI.8 Hence, for pa-tients with predominantly nocturnal reflux, the PPI may be given around dinner time or even at bedtime.

Treatment Failure

There is an increasing prevalence of

PPI failure in GERD patients. The failure is multifactorial, including poor drug compliance, incorrect administration of PPI, nocturnal symptoms, oesophageal hypersensitivity, functional heartburn, psychological comorbidity, concomitant functional bowel disorders (eg, irritable bowel syndrome and functional dys-pepsia), weakly acidic or nonacidic reflux, and extra-oesophageal manifestations.

Patients with erosive oesophagitis respond best to PPI. After 8 weeks of PPI treatment, >94% of patients with oesoph-agitis will be completely healed. Patients with NERD have the lowest response to PPI, especially in the subgroup with func-tional heartburn. Patients with Barrett’s oesophagus should also be treated aggres-sively with PPI, but they responded poorly. Regression of Barrett’s oesophagus is slow or absent in most patients.

Although most believe that acid is the major component in reflux disease, there are patients with symptoms due to weakly acidic or nonacidic reflux. The new multichannel intraluminal impedance (MII) method can detect whether the reflux content is acid, weakly acid or nonacidic, or if the content is gas, liquid or mixed.3,9 It is a catheter-based device similar to the ambulatory 24-hour oe-sophageal pH monitoring device. The catheter includes a few metal rings to measure the impedance, together with two standard pH detectors like the pH monitoring device. The catheter is placed in the lower oesophagus and stomach. Similarly, patients are asked to report reflux symptoms by pressing on the preset buttons. Analysis of the tracings will be able to identify reflux contents and symptom correlations. This method is be-coming increasingly popular, and is espe-cially useful in patients with PPI failure.

Treatment in Extra-oesophageal Manifestations

Clinical studies on GERD-related chronic cough, asthma and LPR are based on small numbers, have different as-sessment criteria for response, and use different types and dosing of PPI. Hence, the results are difficult to interpret, if at all

possible. We carried out a double-blind, randomized, controlled trial on LPR and showed that the use of PPI twice daily led to significant symptom relief at week 6 continuing to week 12, compared with placebo.10 The therapeutic effect was gone after stopping the treatment at week 12, and the symptoms at week 18 returned to pretreatment level. Our recent study on asthma patients showed that 40% also suffered from GERD.11 Those patients with co-existing GERD demon-strated worse asthma control compared with patients without co-existing GERD. In general, we believe that treatment of extra-oesophageal manifestations is difficult, requiring a longer duration and possibly higher dose of PPI. More studies are required.

Conclusion

GERD is a syndrome with heterogeneous population and different manifestations. Many patients, especially those with extra-oesophageal manifestations, may be underdiagnosed and suboptimally managed. Doctors need to be more vigilant in making the diagnosis. Although PPI is the best and mainstay of treatment, the prevalence of PPI failure is increasing and new therapy is needed.

References: 1. Wong BCY, Kinoshita Y. Systematic review on epidemiology of gastro-

oesophageal reflux disease in Asia. Clin Gastroenterol Hepatol 2006;4:398-407.

2. Vakil N, van Zanten S, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: A global evidence based consensus. Am J Gastro 2006;101:1900-1920.

3. Xiao YL, Lin JK, Cheung TK, et al. Normal values of 24-hour combined esophageal multichannel intraluminal impedance and pH monitoring in the Chinese population. Digestion 2009;79:109-114.

4. Wong WM, Lai KC, Lam KF, et al. Prevalence, clinical spectrum and health care utilization of gastroesophageal reflux disease in a Chinese population: A population-based study. Aliment Pharmacol Ther 2003:18:595-604.

5. Wong WM, Lam SK, Hui WM, et al. Long-term prospective follow-up of endoscopic esophagitis in southern Chinese – prevalence and spectrum of the disease. Aliment Pharmacol Ther 2002;16:2037-2042.

6. Wong WM, Lam KF, Lai KC, et al. A validated symptoms questionnaire (Chinese-GERDQ) for the diagnosis of gastro-oesophageal reflux disease in the Chinese population. Aliment Pharmacol Ther 2003;17:1407-1413.

7. Wang WH, Huang JQ, Zheng GF, et al. Is PPI test a better diagnostic approach to noncardiac chest pain related to gastroesophageal reflux? A meta-analysis. Arch Intern Med 2005;165:1222-1228.

8. Wilder-Smith C, Röhss K, Bokelund Singh S, Sagar M, Nagy P. The effects of dose and timing of esomeprazole administration on 24-h, daytime and night-time acid inhibition in healthy volunteers. Aliment Pharmacol Ther 2010;32:1249-1256.

9. Xiao YL, Lin JK, Cheung TK, et al. Reflux profile of Chinese gastro-esophageal reflux disease patients with combined multichannel intra-luminal impedance-pH monitoring. J Gastroenterol Hepatol 2009;24: 1113-1118.

10. Lam PK, Ng ML, Cheung TK, et al. Rabeprazole is effective in treating laryngopharyngeal reflux. Clin Gastroenterol Hepatol 2010;8:770-776.

11. Cheung TK, Lam B, Lam KF, et al. Gastroesophageal reflux disease is associated with poor asthma control, quality of life, and psychological status in Chinese asthma patients. Chest 2009;135:1181-1185.

THE SOCIETY OF PHYSICIANS OF HONG KONG President: Dr. Lam Tat Chung, Paul (林達聰醫生) FRCP, FHKAM(Medicine), FHKAM(Psych)

CME FOR MEDICAL DOCTORS

Place: The Langham Hotel, 8 Peking Road, TST, Kowloon CME points under application.Enquiry: 2526 2626 (no telephone registration) First come first serve basis. Pre-registration is required Non member please pay $50 on admission. Do not mail your cheque No confirmation will be sent for registration. Unsuccessful applicants will be notified.

Registration form: Fax to 2856 2728 Attention: Ms. Sally Wong of Nycomed (Hong Kong)Limited

Web registration and further details: www.SOPHYSICIANSHK.org□ I wish to attend Sunday Symposium on August 14, 2011 (Non-member $50) □ I wish to attend Sunday Symposium on September 4, 2011 (Non-member $50) □ I wish to attend Sunday Symposium on October 9, 2011 (Non-member $50)

Name of Doctor (Surname first):___________________________________ Tel:_______________ Free for Members and Associate Members on presentation of valid membership cards of

THE SOCIETY OF PHYSICIANS OF HONG KONG

August 14, 2011 Sunday Symposium 11:00 am-4:30 pm Lunch 1:00-2:00pm The role of RAAS in BP lowering and cardiovascular risk reduction

Dr. Mak Yiu Kwong, Gary, FRCP (麥耀光醫生) Update on the management of type 2 DM Dr. Tong Chun Yip, Peter, PhD, FRCP (唐俊業醫生)COPD Treatment: What’s new? Dr. Lam Bing, FRCP (林冰醫生) Bisphosphonates and atypical fracture: An update Dr. Ip Tai Pang, FHKAM (葉大鵬醫生) Sponsors: Takeda Pharmaceuticals Taiwan, Ltd-Hong Kong Branch

Nycomed (Hong Kong)Limited

September 4, 2011 Sunday Symposium 11:00am-4:30 pm Lunch 1:00-2:00 pm The milestone of gene therapy in cancer treatment Dr. Li Long Jiang (李龙江醫生) Gendicine – a paradigm shift in cancer management Dr. Shiu Cho Tak, Wesely, MD, FRCP (邵袓德醫生) Latest update on Alzheimer’s disease management Dr. Tam Kui Fu, FRCP (譚鉅富醫生) Rational use of proton pump inhibitors: An update on clopidogrel-PPI drug interaction Dr. Ng Fook Hong, MD, FRCP (吳福康醫生) Advance in the management in allergic rhinitis and sinusitis Dr. Chow Chun Kuen, FHKAM (周振權醫生)

Sponsors: Modec Genetics Inc. Novartis Pharmaceuticals (Hong Kong) Limited Nycomed (Hong Kong) Limited

October 9, 2011 Sunday Symposium 11 :00am-4:30 pm Lunch 1:00-2:00 pm Updates on non-Hodgkin’s lymphoma Dr. Liu Sung Yu, Herman, FRCP (廖祟瑜醫生) Optimizing the management of chronic myeloid leukaemia with targeted therapy

Dr. Chen Yi Tin, FRCP (陳以天醫生) Lymphoproliferative disorders—the basics Dr. Tse Wai Choi, Eric, PhD, FRCPath, FRCP(謝偉財醫生) Current unmet therapeutic needs and novel treatment in osteoporosis management Dr. Chan Kwok Wing. Fredriech, FRCP (陳國榮醫生)Sponsors: Novartis Pharmaceuticals (Hong Kong) Limited Cephalon Inc. GlaxoSmithKline Limited Lee’s Pharmaceutical (HK) Limited

JOURNAL OF THE SOCIETY OF PHYSICIANS OF HONG KONG

July 2011 • Vol. 3 • No. 4

1

Niacin for the Treatment of Dyslipidaemia and Atherosclerosis

Dr. Miao Hu, Teresa (胡淼博士)

BSc, PhD

Postdoctoral Fellow, Department of Medicine and Therapeutics, Chinese University of

Hong Kong


Professor Brian Tomlinson (湯寧信教授)

BSc, MBBS, MD, FRCP (Lond, Edin, Glasg), FACP, FHKCP, FCP, FHKAM (Med)


Head, Division of Clinical Pharmacology, Department of Medicine and Therapeutics,

Chinese University of Hong Kong


References:

1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors

associated with myocardial infarction in 52 countries (the INTERHEART study): Case-

control study. Lancet 2004;364:937-952.

2. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive

lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26

randomised trials. Lancet 2010;376:1670-1681.

3. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL

cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310.

4. Carlson LA. Nicotinic acid: The broad-spectrum lipid drug. A 50th anniversary

review. J Intern Med 2005;258:94-114.

5. Myers CD, Kamanna VS, Kashyap ML. Niacin therapy in atherosclerosis. Curr Opin

Lipidol 2004;15:659-665.

6. Gille A, Bodor ET, Ahmed K, Offermanns S. Nicotinic acid: Pharmacological

effects and mechanisms of action. Annu Rev Pharmacol Toxicol 2008;48:79-106.

7. Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol

2008;101:20B-6B.

8. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in

atherogenic dyslipidemia: Pharmacotherapy to reduce cardiovascular risk. Pharmacol

Ther 2010;126:314-345.

9. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid

alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis

2010;210:353-361.


July 2011 • Vol. 3 • No. 4

2

10. Oberwittler H, Baccara-Dinet M. Clinical evidence for use of acetyl salicylic acid in

control of flushing related to nicotinic acid treatment. Int J Clin Pract 2006;60:707-715.

11. Dunn RT, Ford MA, Rindone JP, Kwiecinski FA. Low-dose aspirin and ibuprofen

reduce the cutaneous reactions following niacin administration. Am J Ther 1995;2:478-

480.

12. Olsson AG. Laropiprant plus niacin for dyslipidemia and prevention of

cardiovascular disease. Expert Opin Pharmacother 2010;11:1715-1726.

13. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy

and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic

patients. JAMA 1994;271:672-677.

14. Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, and tolerability of

once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes:

Results of the assessment of diabetes control and evaluation of the efficacy of niaspan

trial. Arch Intern Med 2002;162:1568-1576.

15. Fazio S, Guyton JR, Lin J, Tomassini JE, Shah A, Tershakovec AM. Long-term

efficacy and safety of ezetimibe/simvastatin coadministered with extended-release

niacin in hyperlipidaemic patients with diabetes or metabolic syndrome. Diabetes Obes

Metab 2010;12:983-993.

16. Watts GF, Chan DC. Of mice and men: Blowing away the cobwebs from the

mechanism of action of niacin on HDL metabolism. Arterioscler Thromb Vasc Biol

2008;28:1892-1895.

17. Ganji SH, Tavintharan S, Zhu D, Xing Y, Kamanna VS, Kashyap ML. Niacin

noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. J Lipid Res

2004;45:1835-1845.

18. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular

risk factor: current status. Eur Heart J 2010;31:2844-2853.

19. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart

disease. JAMA 1975;231:360-381.

20. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug

Project patients: Long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-1255.

21. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the

Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A double-

blind, placebo-controlled study of extended-release niacin on atherosclerosis

progression in secondary prevention patients treated with statins. Circulation

2004;110:3512-3517.

22. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin

and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med

Res Opin 2006;22:2243-2250.

23. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and

carotid intima-media thickness. N Engl J Med 2009;361:2113-2122.


July 2011 • Vol. 3 • No. 4

3

24. Whitney EJ, Krasuski RA, Personius BE, et al. A randomized trial of a strategy for

increasing high-density lipoprotein cholesterol levels: Effects on progression of coronary

heart disease and clinical events. Ann Intern Med 2005;142:95-104.

25. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins,

or the combination for the prevention of coronary disease. N Engl J Med

2001;345:1583-1592.

26. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of

coronary atherosclerosis during treatment of familial hypercholesterolemia with

combined drug regimens. JAMA 1990;264:3007-3012.

27. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a

result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N

Engl J Med 1990;323:1289-1298.

28. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic

Heart Disease Secondary Prevention Study by combined treatment with clofibrate and

nicotinic acid. Acta Med Scand 1988;223:405-418.

29. Blankenhorn DH, Selzer RH, Crawford DW, et al. Beneficial effects of colestipol-

niacin therapy on the common carotid artery. Two- and four-year reduction of intima-

media thickness measured by ultrasound. Circulation 1993;88:20-28.

30. National Institute of Health News (May 26, 2011). NIH stops clinical trial on

combination cholesterol treatment. http://www.nih.gov/news/health/may2011/nhlbi-

26.htm. Accessed 27 May 2011.

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