胃食道反流疾病的西醫藥治療 王衛民醫生 Raymond WM Wong MBBS(HK) MD(HK) PhD(HK) FRCP(Lond, Edin, Glasg) FACG FACP
王衛民醫生現為聖保祿醫院腸胃肝臟科顧問醫生及香港大學李嘉誠醫學院內科學系名譽臨床醫學副教授
胃食道反流疾病 (GERD) 1. 併發症 2. 令人困擾的症狀 Montreal Classification 2006
胃酸倒流的原理 食道蠕動及唾液分泌 下食道括約肌鬆弛 胃酸 胃部排空緩慢
Hiatus hernia results in more reflux episodes and esophageal acid exposure 食管裂孔疝
胃食道反流性疾的原理
括約肌 失守 連接我們食道與胃部的肌肉賁門叫下食道括約肌, 專責防止胃內食物及胃酸倒流入食道, 如果下食道括約肌鬆弛, 就會令到胃酸倒流入食道 而食道的黏膜十分脆弱, 若長久受到胃酸刺激會令食道發炎 潰瘍 出血 及出現一種癌前病變的情況 ( 巴洛氏食道 ) 巴洛氏食道是指一些病人的正常食道細胞被不正常的細胞取代了, 而巴洛氏食道與食道癌有密切關係
胃酸倒流引致的食道炎
於四年半內, 在香港瑪麗醫院之统計中, 有 16,606 位患者進行內窺鏡測試 4 3 ( 食道癌 ) Percent 2 1 0 食道炎食道狹窄巴洛氏食道 Wong WM et al. APT 2002
胃食道反流疾病之典型徵狀 胸口灼痛 胃酸倒流 噯氣 有胃酸的感覺 一般來說, 胃酸倒流入食道情況以睡覺時比日間嚴重, 原因是地心吸力關係, 令我們平臥在床上時胃酸更容易倒流入食道
胃食道反流疾病之非典型徵狀 非心臟病胸口痛 慢性咳嗽 / 哮喘 聲嘶 警號之徵狀 體重下降, 吞嚥困難, 吞嚥時感到疼痛, 嘔血, 窒息感覺 需要盡快施行內視鏡檢查
高危人士 暴飲暴食 喝過多咖啡及食太辣食物者 ; 妊娠婦女及過度肥胖人士 ; 常吃宵夜之人士 ; 吸煙 酗酒之人
Weekly symptoms of heartburn / acid regurgitation 2013 El-Serag HB, et al. Gut Online July 13,2013
每星期受胸口灼痛 / 胃酸倒 流的症狀影響 19.8% 2.5% 美國 香港 Locke et al. 1997 Wong WM, et al. 2003
飲食習慣 東方與西方
2011 * Prevalence of GERD ( 胃食道反流疾病的流行程度 ) Annual Estimated Population Monthly Estimated Population Weekly 2011 年香港的總人口 700 萬人 6.7% 3.3% 1.3% 每星期均有一次受胃食道 Estimated Population 36.5% 2.58 mil 12.2% 862,500 3.8% 266,000 反流疾病的症狀影響 266,000 每月均有一次受胃食道 2003 34.1% 2.31 mil 10.1% 686,800 2.7% 183,600 反流疾病的症狀影響 854,000 2002 29.8% 2.02 mil 8.9% 605,200 2.5% 170,000 Wong WM APT 2004;20:803-12, Wong WM APT 2003:18:595-604. *V Tan, J Clin Gastroenterol 2015 Mar 6 [Epub ahead of print]
診斷方法
內視鏡檢查
內視鏡檢查 對診斷食道炎非常有用. 大部份患有胃食道反流病之病患者在內視鏡檢查中無發現患上食道炎. 內視鏡檢查是一種介入和昂貴的檢查, 而且在檢查中會有少許不舒適.
食道測壓計
24 小時活動胃酸監測儀 食道下端測到的酸鹼 值小於 4.0, 即表示有 胃酸倒流至食道 探測酸鹼度之膠導管
24 小時活動胃酸監測儀 感覺到胸口灼痛 胃酸倒流至食道
24 小時活動胃酸 監測儀 接受檢查者不可以淋浴及防礙睡眠 鼻導管測試時會引致不適
RF 遙控測量術 Bravo 酸鹼度測量系統 無線之膠囊 無喉管的酸鹼度 測量系統 如傳呼機大小之接收器 接受檢查者可以淋浴及不防礙睡眠
Bravo 酸鹼度測量系統 酸鹼度膠囊與接收器 酸鹼度膠囊會將測到的資料傳送到一個像傳呼機大小之接收器內 此方法可免除用鼻導管測試時所引起之不舒適
膠囊放送系統 真空抽吸器 接收器
Bravo 酸鹼度測量系統 Capsule Attachment Step 1 Step 2 Step 3 Step 4 Step 5 Position Bravo Capsule Apply Suction Advance Pin Release Capsule Begin ph Recording
Bravo 無線酸鹼度膠囊 膠囊之長度為 2.6cm
Bravo膠囊 患者進行BRAVO 膠囊安裝
Impedance Technology Fundamentals 電阻抗監測系統 Bolus Spanning Impedance Contacts Food Bolus High conductivity Low impedance Current Generator
Impedance Technology Fundamentals 電阻抗監測系統 I m p e d a n c e Bolus Entry Bolus Exit Bolus Present Time Impedance Contacts
Impedance ph Catheter 聯合多通道腔內 電阻抗及酸鹼度 測量系統 17 cm 15 cm 9 cm 7 cm 5 cm 3 cm 6 impedance channels ph - 5 cm 1 ph channel
電阻抗監測系統 吞咽 反流 Bolus Entry 食團運動 Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry Bolus Entry 食團運動
Acid 胃酸倒流至食道 Reflux Episode Impedance @ 17 cm 逆行食團運動 Impedance @ 15 cm Impedance @ 9 cm 酸鹼值小於 4.0 Impedance @ 7 cm Impedance @ 5 cm Impedance @ 3 cm ph @ 5 cm ph 4.0 threshold 34 34
冶療方法
胃食道反流疾病之冶療方法 改變生活習慣 胃動力促進劑 制酸劑 H 2 受體抗制劑 質子泵抑制劑 (PPI) 外科手術
保持良好的生活習慣 少食多餐, 每餐不要吃得過飽, 保持正常體重, 肥胖者以運動減肥 避免吃油炸 肥膩及辛辣的食物或酸性飲品, 如檸檬 番茄 薄荷 洋蔥及蒜 咖啡 濃茶 巧克力 吸煙及酗酒 進餐後勿立即睡覺, 勿平臥或彎曲身體, 若平躺睡覺時可將頭及胸部墊高一些 睡前 4 小時勿進食及戒宵夜習慣
制酸劑 只可幫助減輕症狀較為輕微及偶然發生的胃食道反流性疾病. 制酸劑不能有效冶療 不能有效冶療有頻密胃食道反流病徵的病人. 中度或嚴重胃食道反流疾病之病人 制酸劑不能冶愈食道炎.
質子泵抑制劑 質子泵 Proton pump Inhibition of proton pump Activation Concentration H + Inhibition of acid secretion Gastric gland 胃酸分泌細胞 PPI (inactive) Parietal cell Canalicular space Blood
質子泵抑制劑為最有效冶療 食道炎之藥物 累積冶愈率 (%) 100 90 80 70 60 50 40 30 20 10 0 7635 位患有食道炎之病人 0 2 4 6 8 10 12 質子泵抑制劑 PPI H2 受體抗制劑 H2B 對照組 Placebo Weeks Chiba. Gastroenterology 1997
質子泵抑制劑為最好之維持劑 90 80 維持治癒的比率 (%) 70 60 50 40 30 20 10 0 Ome 20 mg o.m. 質子泵抑制劑 Ome 10 mg o.m. Ranitidine 150 mg b.i.d. H2 受體抗制劑 Placebo 對照組 Carlsson et al. (1997)
質子泵抑制劑 維持治癒的比率 50% 按需要服用冶療法 40% 30% 20% 10% 0% Talley et al. 2002 Esomeprazole 40 Esomeprazole 20 Placebo 質子泵抑制劑 對照組
質子泵抑制劑 - 治療無效? 每日服用一次質子泵抑制劑, 而病徵持續的機會是多少呢? 無效 30% Carlsson et al. Eur J Gastroenterol Hepatol 1998. Fass et al. Aliment Pharmacol Ther 2000. 70% PPI Responder PPI Failure
每日服用一次質子泵抑制劑, 而患者病徵持續 依從服藥的指引 ( 在服用初期是有効的 )
治療胃食道反流疾病 - 不依從服藥指引是非常普遍的 27.8 29.6 3.7 38.9 N = 100 進食前一小時飯後睡覺前需要時才服用 Gunaratnam et al. Aliment Pharmacol Ther 2006;23(10):1473-1477
治療無效, 應該甚辨?
質子泵抑制劑只能夠抑制 活躍的質子泵 PPIs only bind to active proton pumps 1 PPI 未激活的質子泵 PPI 1. Del Valle J et al. Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2003:1321-1376.
質子泵抑制劑的藥物半衰期 ~1-2 Hours 1 Any proton pumps activated after PPI concentrations fall below effective plasma levels may not be inhibited 1 Plasma Concentration 2 PPI (hypothetical) Effective plasma level Time 1. Sachs G. Pharmacotherapy. 1997;17:22-37. 2. Brenner GM. Pharmacokinetics. In: Brenner GM. Pharmacology. 1st ed. Philadelphia, PA: WB Saunders Co; 2000:9-25.
服用一個劑量的質子泵抑制劑 1/4 質子泵仍有製造胃酸的能力 AT LEAST OF ACID PRODUCTION CAPACITY MAY NOT BE SHUT DOWN BY A PPI DOSE 1-3 PPIs only inhibit active proton pumps Not all proton pumps are active at any given time 1-3 1. Blair JA et al. J Clin Invest. 1987;79:582-587. 2. Sachs G. Pharmacotherapy. 1997;17:22-37. 3. Del Valle J et al. Acid peptic disorders. In: Yamada T et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:1321-1376.
American Gastroenterological Association (AGA) Survey 1064 GERD patients Physician-made diagnosis of GERD Receiving once-daily PPI for 3 months 10-min online patient survey designed to assess Symptom control Use of over-the-counter (OTC) remedies Physician-patient dialogue about GERD American Gastroenterological Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.
Nearly 40% of Patients on Once-Daily PPI Therapy Have Breakthrough Symptoms Patient-Reported Symptoms on Once-Daily PPI Therapy (N=1064) No Breakthrough Symptoms Breakthrough Symptoms American Gastroenterological Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.
Breakthrough Symptoms Are Often Experienced at Night Most Patients With Breakthrough Symptoms Experience Them at Night At Night While Sleeping During the Day In the Morning American Gastroenterological Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.
56% of Patients With Breakthrough Symptoms Use Adjunctive OTC Medications Additional Medications Used to Manage Breakthrough Symptoms 49% OTC Antacid 7% OTC Acid Reducer* OTC Antacid / Acid Reducer 現時的質子泵抑制劑的限制 Another Prescription 1. 需要餐前 30 至 60 PPI分鐘服用 2. 很多時侯都需要服用兩次 Nothing 3. 半衰期很短 Other OTC products mentioned: Alka-Seltzer, Maalox, Mylanta, Pepcid Complete, Pepto-Bismol, Rolaids, TUMS. *OTC acid reducer includes OTC acid reduction agents, OTC H 2 RAs, and OTC PPIs. American Gastroenterological Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.
Dexlansoprazole Consists of a Dual Delayed Release (DDR) Formulation 右蘭索拉唑緩釋膠囊 Dexlansoprazole is the R-enantiomer of lansoprazole 一種具有雙重緩釋效果的質子泵抑制 劑, 有兩種獨立的藥物釋放方式 Artistic rendition. Not an actual representation of granules. 1. Dexlansoprazole Prescribing Information, Takeda Pharmaceuticals North America, Inc. Deerfield, IL. 2009. 2. Metz D, et al. Aliment Pharmacol Ther. 2009;29:928-937.
DEXILANT (雙重緩釋效果的質子泵抑制劑) DDR formulation of DEXILANT allows each type of granule to release medication at different ph levels1 The Enteric Coating of Each Type of Granule Dissolves at a Different ph in the GI Tract1,2 Granule 1 Granule 2 Sugar sphere Active-coating layer ph 5.5 ph 6.75 Middle (protective) layer Enteric coating layer 1 GI=gastrointestinal. Enteric coating layer 2 Artistic rendition of granules. 1. DEXILANT Package Insert. 2. Vakily M et al. Curr Med Res Opin. 2009;25:627-638. 55
一種具有雙重緩釋效果的質子泵抑制劑, 有兩種獨立的藥物釋放方式 The DDR formulation results in a plasma concentration-time profile with two distinct peaks Granule 1 comprises 25% of total dose and is released at ph 5.5 within 2 hours of dosing 2 Release 1 Granule 2 comprises 75% of total dose and is released at ph 6.75 several hours after dosing Release 2 1. DEXILANT (dexlansoprazole) Prescribing Information, Takeda Pharmaceuticals North America, Inc. Deerfield, IL. 2009. 2. Data on file, Takeda Pharmaceuticals North America, Inc. Deerfield, IL
Dexlansoprazole maintains high plasma concentrations longer than esomeprazole (n = 43) (n = 44) DDR formulation allows dexlansoprazole to have: 10% increase in duration with ph>4 compared with esomeprazole Reference: Kukulka M et al. Clin Exp Gastroenterol 2011;4:213-220.
Dexilant ( 右蘭索拉唑緩釋膠囊 ) 八星期內的食道炎治愈率 n=656 n=639 n=634 n=648 n=657 n=652 n=1,304 n=1,296 n=1,286 Study 1 Study 2 Life Table Analysis Combined Healing (%) 86 92 92 92 93 95 89 93* 94* n 684 673 665 672 685 680 1,356 1,358 1,345 P < 0.05 after adjusting for the number of doses compared. Pairwise treatment comparisons performed with Cochran-Mantel-Haenszel test for crude rate analysis and with log-rank tests for life table analysis. Sharma P, et al. Aliment Pharmacol Ther. 2009;29:731-741.
對食道炎病徵的控制 - 燒心感,火燒心 Dexlansoprazole 30 mg Provided 96% Heartburn-Free 24-Hour Periods in a 6-Month Study Median Percentage of 24-Hour Heartburn-Free Periods of the Maintenance of Healed EE Study Overall Treatment1 Median Heartburn-Free 24-h Periods, % 100 80 * 96 Dexlansoprazole 30 mg Placebo 60 *P<.0025 vs placebo2 40 29 20 0 n=132 n=141 Metz et al, Aliment Pharmacol Ther 2009; 29: 742-54 TAK_OEC 59
Potassium-competitive acid blockers (P-CABs) 鉀離子競爭性胃酸抑制劑 Block gastric H / K -ATPase by reversible and K - competitive ionic binding. Rapid onset of anti-secretory effect. Maximal antisecretory effect may be seen after first dose.
鉀離子競爭性胃酸抑制劑 與質子泵抑制劑之比較 P-CABs 鉀離子競爭性胃酸抑制劑 Acts directly on the H/K ATPase Prodrug PPIs 質子泵抑制劑 Superconcentration in parietal cell acid space (100,000 fold of plasma) Binds competitively to the K- binding site of H/K ATPase Duration of effect related to halflife of drug in plasma Full effect from the first dose Concentrate in parietal cell acid space (1,000 fold of plasma) Binds covalently to H/K ATPase Duration of effect related to the half-life of the Sulphenamideenzyme complex Full effect after repeated doses
鉀離子競爭性胃酸抑制劑 Revaprazan (Revanex) 鹽酸瑞伐拉贊, Licensed in South Korea (Yuhan). Vonaprazan 沃諾拉贊 Licensed in Japan. Phase III study of Vonaprazan 20mg vs Lansoprazole 30mg once daily in the treatment of patients With Erosive Esophagitis in China (Jan, 2017).
Baclofen 巴氯芬 For Non-Acidic Reflux 弱酸反流 GABA-B agonists. Reduces TLESR. Inhibitory Effect of Oral Baclofen 40 mg/day on Postprandial TLESRs Mild gastrokinetic. 40-50% reduction in TLESR rate. Improve GERD symptoms. Start with 10mg at bed time. Can increase up to 20mg tid. Watch for neurological side effects hypotonia, drownsiness TLESRs (num ber/hour) 10 8 6 4 2 0 * * 1-60 61-120 121-180 1-180 Time (min) * * Placebo Baclofen Lidums I et al. Gastroenterology. 2000;118:7 13. Fass R. Clin Gastroenterol Hepatol 2012;10:338-45
The Stretta Technique Apply radiofrequency energy delivery to the distal oesophagus -> decrease esophageal sensitivity to acid. 非燒蝕射頻能量 Improvement of esophageal symptoms, decrease in PPI use, but no effect on esophageal acid exposure. Utley et al.gie 2000
內窺鏡結紮 Martinez-Serna et al. GIE 2000
內窺鏡結紮
LINX Reflux Management System 磁環系統 LINX consists of magnetic beads that are connected by titanium links that allow the beads to open during a swallow or belch. The force of magnetic attraction exerts forces to strengthen the LES.
LINX Reflux Management System 磁環系統 Reinforces the LES restoring the barrier function Expands during swallow allowing food to enter stomach Highest Magnetic Resistance Lowest Magnetic Resistance
EndoStim Implant 植入式脈衝發射器 The EndoStim system automatically delivers tiny electronic pulses from the implanted pulse generator to the weak LES muscle. The pulses stimulate the muscle to function as a healthy LES, opening for swallowing, belching, and other normal behaviors, but remaining closed at other times. Investigational device, currently not FDA approved or CE Marked
外科手術
結論 Conclusions GERD is a growing problem in Asia. 胃食道反流疾病在亞洲的流行程度遠低於西方國家, 但有上升的趨勢 New diagnostic modality available. 現時有新的診斷方法 PPIs are currently the optimal medical therapy. 質子泵抑制劑是最有效的藥物 Newer PPI / P-CABS and new endoscopic techniques potentially promising. 在不久將來, 新的藥物和手術為治療胃食道反流疾病帶來新的希望