Gastroenterologi 2018;154:302-318

Penatalaksanaan Penyakit Refluks Gastroesofageal

GERD

C.Prakash Gyawali Ronnie Fass²

'Divisi Gastroenterologi, Fakultas Kedokteran Universitas Washington, St. Louis, Missouri; dan Divisi Gastroernterologi dan
Hepatologi, Pusat Esofagus dan Menelan, Case Western Reserve University, MetroHealth Medical Center, Cleveland, Ohio

Penatalaksanaan penyakit refluks gastroesofageal (GERD) terapi. Adanya esofagitis erosif dikaitkan dengan respons terhadap
biasanya dimulai dengan uji empiris terapi penghambat pompa terapi antirefluks.° Selain itu, peningkatan waktu pemaparan asam
proton (PPI) dan tindakan gaya hidup pelengkap, untuk pasien tanpa esofagus distal (AET) memprediksi perbaikan gejala setelah terapi
gejala yang mengkhawatirkan. Optimalisasi terapi (meningkatkan antirefluks; kemungkinan asosiasi gejala positif melengkapi
kepatuhan dan waktu pemberian dosis PPI), atau meningkatkan peningkatan AET dalam keadaan ini.° Dengan menggunakan 2
dosis PPI menjadi dua kali sehari dalam keadaan tertentu, dapat parameter ini, GERD dapat dikarakterisasi menjadi fenotipe
mengurangi gejala yang persisten. Pasien dengan gejala lanjutan berbeda yang mempunyai implikasi penatalaksanaan." Lebih dari
dapat dievaluasi dengan endoskopi dan tes fisiologi esofagus, untuk dua pertiga pasien dengan peningkatan AET memiliki respons
mengetahui fenotipe penyakitnya dengan lebih baik dan gejala terhadap pengobatan medis atau bedah. terapi antirefluks.
mengoptimalkan pengobatan. Fundoplikasi laparoskopi, augmentasi Di sisi lain, metrik refluks fisiologis menunjukkan dasar fungsional
sfingter magnetik, dan terapi endoskopi dapat bermanfaat bagi
untuk Gejala. 9.10 dan kurang dari 50% pasien dengan beban
pasien dengan GERD yang berkarakteristik baik. Pasien dengan
refluks fisiologis dan hubungan gejala-refluks negatif
penyakit fungsional yang mirip atau mirip dengan GERD dapat
melaporkan penurunan gejala pada pasien dengan refluks
diobati dengan neuromodulator (terutama antidepresan), atau
fisiologis (hipersensitivitas refluks), hasil pengobatan bervariasi.
intervensi psikologis (psikoterapi, hipnoterapi, terapi perilaku kognitif).
Kami meninjau strategi manajemen untuk GERD dan pendekatan
Pendekatan pengobatan GERD di masa depan mencakup
terhadap GERD Gejala yang bertahan meskipun manajemen
penghambat asam kompetitif kalium, zat pereduksi refluks, pengikat
asam empedu, injeksi zat inert ke dalam sambungan esofagogastrik, penyakit tampaknya memadai.
dan stimulasi listrik pada sfingter esofagus bagian bawah.

Gaya Hidup
Kata Kunci: Penyakit Refluks Gastroesofageal; Penghambat Pompa Proton; Manajemen
Antagonis Reseptor Histamin-2; Bedah Antirefluks.

penyakit refluks astroesophageal (GERD) adalah diagnosis U yang

umum terjadi pada semua kelompok umur dan jenis kelamin, dengan
perkiraan tingkat prevalensi 8% hingga 33% di seluruh dunia.' Beban ekonomi
sebesar $9 hingga $10 miliar per tahun merupakan biaya langsung di Amerika
Serikat saja, terutama terkait dengan penggunaan penghambat pompa proton (
PPI). PPl diresepkan secara empiris sebagai pendekatan diagnostik awal
pragmatis untuk pasien dengan gejala khas GERD,* serta gejala atipikal (nyeri
dada nonkardiak, batuk kronis, suara serak, tenggorokan berdehem, mengi).
Kadang-kadang, pasien diberikan dua kali lipat dosis standar; resep yang
berlebihan dan penggunaan PPl yang tidak tepat merupakan masalah yang
tersebar luas."

Tes esofagus dapat mengelompokkan pasien dengan GERD ke dalam

kategori penatalaksanaan untuk penggunaan antirefluks yang tepat
Januari 2018

mengikuti. Beberapa pasien melaporkan makanan tertentu yang menyebabkan

Gejala GERD, termasuk jeruk, makanan pedas, kafein, coklat, dan makanan
berlemak. Namun, pembatasan pola makan secara luas hanya memiliki manfaat
terbatas dalam mengurangi gejala esofagus."
Hubungan antara pertambahan berat badan dan gejala GERD telah
diketahui dengan baik dalam studi populasi; penambahan berat badan juga
dikaitkan dengan peningkatan risiko erosif -15
esofagitis dan esofagus Barrett (BE).* Bahkan penambahan berat badan yang
sedikit pun dapat memperburuk gejala GERD baik pada individu yang tidak
mengalami obesitas maupun yang mengalami obesitas, khususnya pada wanita.
Akibatnya, penurunan berat badan dan pengurangan lingkar pinggang telah
terbukti mengurangi gejala GERD, paparan asam esofagus, dan kejadian refluks
pasca-prandial.17-20
Karena gejala terobosan di malam hari biasanya dilaporkan oleh pasien
21
yang gagal dalam terapi GERD, penekanan pada modifikasi gaya hidup pada
malam hari sangatlah penting. Tidur dengan ujung kepala tempat tidur
ditinggikan, menggunakan balok di bawah tiang ranjang atau baji, mengurangi
episode refluks, dengan pembersihan asam yang lebih cepat dan gejala
refluks yang lebih sedikit dibandingkan dengan tidur datar. AET lebih lama,
dan pembersihan asam lebih lambat ketika berbaring di atas tempat tidur. sisi
kanan dibandingkan dengan kiri, kemungkinan karena persimpangan
esofagogastrik (EG) berada di atas tingkat kumpulan asam saat berbaring
miring ke kiri. Tindakan lainnya termasuk mematikan lampu kamar tidur dan
22-24
meminimalkan gangguan terhadap tidur normal. Meskipun ada hubungan
antara episode refluks pasca-prandial dan gejala GERD, tidak ada bukti
konklusif bahwa menghindari makan larut malam dapat mengurangi beban
asam esofagus.6
304 Gyawali dan Fass

Tabel 1.Respon Gejala GERD dan Esofagitis terhadap Penekanan Asam pada Uji Acak Terkontrol

Respon terhadap
pengobatan, %

Inhibitor pompa proton

Mulas yang belum
diselidiki Mulas tanpa esofagitis5
Mulas dengan esofagitis
Esofagitis erosif
Regurgitasi56
Nyeri dada nonkardiak, tes GERD positif Nyeri
dada nonkardiak, tes GERD negatif Batuk kronis1 58

Gejala laring®2

Antagonis Reseptor Histamin-2

Sakit maag yang tidak diselidiki5
Sakit maag
tanpa esofai Sphagitis erosif55
Tabel 2. Risiko Terapi Inhibitor Pompa Proton Jangka Panjang
 306 Gyawali dan Fass

relaksasi (TLESRs), dan mengurangi kejadian refluks pada sukarelawan sehat

serta pasien dengan GERD.'° Namun, baclofen dikaitkan dengan efek
samping sentral (somnolen, pusing) yang mungkin membatasi kegunaannya.
Upaya untuk mengembangkan analog dengan efek samping sentral yang lebih sedikit
telah dibatasi oleh kurangnya kemanjuran dan toksisitas hati. Namun
demikian, jika dapat ditoleransi, baclofen merupakan pilihan bagi pasien yang
gejalanya tetap ada meskipun telah menjalani terapi PPI.

Pengobatan Tambahan
Januari 2018

beban refluks dan gejala GERD selain mengurangi berat badan dan
penyakit penyerta terkait obesitas. 07 Pilihan ini telah digunakan baik
sebagai pendekatan bedah awal maupun setelah fundoplikasi gagal.0
Operasi bypass Roux-en-Y umumnya lebih aman, dalam hal komplikasi
di rumah sakit yang lebih rendah, dibandingkan fundoplikasi laparoskopi
pada pasien obesitas yang tidak sehat, sedangkan biaya rumah sakit,
lama rawat inap, dan angka kematian sebanding. Sebaliknya, prosedur
109
pelapisan lambung menambah mekanisme refluks dan secara konsisten
dapat memperburuk gejala GERD.
 308 Gyawali dan Fass

GERD
Januari 2018

diperlukan untuk mendapatkan manfaat maksimal dari obat ini (

Gambar 1).
Memisahkan atau menyebarkan dosis standar PPI telah terbukti
meningkatkan kontrol pH intragastrik. Misalnya, esomeprazol yang diberikan
dalam dosis terpisah (20 mg sebelum sarapan dan makan malam)
menghasilkan kontrol pH intragastrik yang lebih baik dibandingkan dengan
dosis standar 40 mg sebelum sarapan.
PH intragastrik >4 dicapai oleh 76,5% pasien yang menggunakan dosis terpisah vs
68,8% yang menggunakan dosis tunggal; median pH intragastrik adalah 4,9 pada
pasien yang menggunakan dosis terpisah vs 4,8 pada mereka yang menggunakan
dosis tunggal.2 Yang terpenting, dosis terpisah memberikan kontrol yang lebih baik
terhadap pH intragastrik pada malam hari. Pasien yang memakai rabeprazole 10
mg 4 kali sehari memiliki median pH intragastrik yang lebih tinggi (6,6)
dibandingkan pasien yang memakai 20 mg dua kali sehari (pH 5,7) atau 40 mg
sekali sehari (4,8).3 Namun, korelasi klinis antara pH intragastrik dan pengurangan
gejala tidak tersedia, dan peningkatan frekuensi pemberian PPl dapat mengurangi
kepatuhan terapi secara keseluruhan.

Strategi penatalaksanaan lainnya melibatkan peralihan ke merek PPI

alternatif, meskipun perbedaan objektif dalam kemanjuran PPI dapat
diabaikan.* Dalam uji coba secara acak terhadap pasien sakit maag yang
tidak merespons terhadap lansoprazole (30 mg) sekali sehari, pasien
beralih ke esomeprazole dosis tunggal ( 40 mg) memiliki proporsi hari
bebas sakit maag yang sama selama periode 8 minggu dengan pasien
yang menerima lansoprazole dua kali sehari (30 mg) (masing-masing 54,4%
136
vs 57,5%).
Dalam penelitian terpisah, 88% pasien yang menerima PPI dua kali sehari (
formulasi apa pun) berhasil menurunkan dosisnya menjadi dexlansoprazole (
30 mg) sekali sehari.37
Karena semakin banyak pasien yang mengkhawatirkan penggunaan PPI
dalam jangka panjang, dokter dapat mempertimbangkan untuk menambahkan
obat antirefluks alternatif ke dalam PPI sekali sehari.
Penambahan H2 blocker, sukralfat, antasida, agen prokinetik, dan baclofen
pada PPl sekali sehari telah diusulkan untuk mengendalikan gejala,
meskipun hal ini belum diteliti. 11,74,1 38-140 Komorbiditas psikologis,
stres, dan kewaspadaan yang berlebihan memperburuk gejala,
meningkatkan penggunaan layanan kesehatan, dan memengaruhi respons
terhadap pengobatan PPI 141-143 Oleh karena itu, intervensi dini harus
dipertimbangkan pada pasien yang melaporkan kurangnya respons
terhadap PPI sebagian atau seluruhnya perlakuan. Evaluasi oleh psikolog
atau psikiater, sebaiknya yang memiliki keahlian di bidang gangguan
gastrointestinal, dapat mencegah perlunya peningkatan dosis PPI.4*

Ketika gejala tetap ada meskipun terapi PPI sudah dioptimalkan sekali
sehari, strategi yang umum dilakukan adalah meningkatkan dosis menjadi dua
kali sehari, yang didukung oleh sebagian besar komunitas gastroenterologi. D1
Ada manfaat menggandakan dosis:
penyembuhan esofagitis erosif dapat meningkat sebesar 6% hingga 19% dan
penyembuhan mulas dapat meningkat sebesar 22% hingga 26%.31-134 Sebuah
tinjauan Cochrane mengaitkan penggandaan dosis PPI dengan tingkat penyembuhan
yang lebih besar pada pasien dengan esonhacitis erosif namun dengan jumlah yang
dibutuhkan untuk mengobati 25. Pasien yang diberi resep dosis ganda harus
meminum dosis pertama sebelum sarapan dan dosis kedua sebelum makan malam.
 310 Gyawali dan Fass

algoritma penatalaksanaan Rome IV." Evaluasi biasanya dimulai

dengan endoskopi bagian atas, dengan biopsi untuk menyingkirkan
esofagitis eosinofilik."122 Meskipun endoskopi tidak mungkin
menemukan gambaran yang memengaruhi penatalaksanaan,15t esofagitis
eosinofilik dan limfositik, akalasia, kelainan kulit yang melibatkan
esofagus, dan kelainan lain yang tidak umum harus disingkirkan.

Jika hasil endoskopi dengan biopsi negatif, pasien menjalani

pemantauan refluks rawat jalan. Meskipun pemantauan pH atau
impedansi pH di luar terapi sesuai untuk pasien yang sebelumnya tidak
memiliki bukti GERD (GERD yang belum terbukti), pemantauan pH
jangka panjang dengan kapsul pH nirkabel, jika tersedia, dapat
memberikan nilai tambah.56,9,155,156 Sebaliknya, pasien dengan
terbukti GERD (tes pH abnormal dan/atau esofagitis erosif pada
endoskopi bagian atas) harus menjalani pemantauan impedansi pH pada
terapi PPI, 5,9,155,156
AET normal pada pemantauan refluks rawat jalan harus segera dilakukan
manometri esofagus. Jika manometri esofagus tidak mendeteksi kelainan
motorik mayor, asosiasi gejala-refluks pada pemantauan refluks dapat lebih
lanjut mengkarakterisasi gejala nyeri ulu hati, terutama dalam memisahkan
hipersensitivitas refluks (indeks gejala positif untuk refluks asam dan asam
lemah) dari nyeri ulu hati fungsional (gejala negatif). indeks). Hipersensitivitas
esofagus merupakan mekanisme yang mendasari hipersensitivitas refluks dan
nyeri ulu hati fungsional, dan mungkin merupakan penyebab sebagian besar
pasien nyeri ulu hati yang tidak memberikan respons terhadap PPl dua kali
sehari.6,156-158 Pasien dengan GERD yang terbukti dan tidak memberikan
respons terhadap terapi PPl dua kali sehari mungkin mungkin mengalami hal ini.
juga memiliki kelainan fungsional esofagus yang tumpang tindih, jika mereka
memiliki temuan normal pada endoskopi dan AET normal pada pemantauan
refluks rawat jalan."

Mengobati Gangguan Fungsional Esofagus

Semua pasien dengan gangguan esofagus fungsional harus
diyakinkan tentang sifat gejala yang tidak berbahaya. Paling

Nama

Imipramine161
Imipramine162 ,
163
Imipramine
Amitriptyline164, 165
Sertraline166
Sertraline
Paroxetine 168
Januari 2018 Penatalaksanaan Penyakit Refluks Gastroesofageal 311

gejala sakit maag dibandingkan dengan plasebo pada pasien dengan sakit digunakan secara klinis, namun tidak tersedia di Amerika Serikat. Dosis
maag fungsional. Namun, tegaserod tidak lagi tersedia untuk penggunaan klinis. 20 mg menyembuhkan 99% pasien dengan esofagitis erosif dalam 8
Melatonin (6 mg, sekali sehari selama 3 bulan) secara signifikan mengurangi minggu, dibandingkan dengan lansoprazole (30 mg), yang
gejala sakit maag dibandingkan dengan nortriptyline (25 mg) atau plasebo menyembuhkan 95,5% pasien, penyembuhan dipertahankan selama
dalam uji coba secara acak. “78 Dalam sebuah studi label terbuka, sesi 52 minggu pada 90% pasien. Meskipun obat ini memiliki profil
hipnoterapi selama 7 minggu secara signifikan menurunkan kecemasan visceral keamanan yang sangat baik, peningkatan gastrin (hingga tiga kali lipat
dan keparahan gejala pada pasien dengan mulas fungsional. hingga empat kali lipat dari batas atas normal) dilaporkan pada pasien
179
yang menerima dosis 20 mg; signifikansi klinis dari peningkatan ini
Karena gejala disebabkan oleh episode refluks pada pasien dengan tidak jelas. Juga tidak jelas apakah P-CAB lebih efektif dalam
hipersensitivitas refluks, terapi antirefluks medis, endoskopi, dan bedah mengurangi gejala dibandingkan obat penekan asam lainnya.
sering kali dipertimbangkan pada awalnya. Sedikit yang diketahui tentang
dampak perubahan pola makan dan gaya hidup. Seperti pada pasien IW-3718 adalah formulasi retensi lambung yang sedang diselidiki dari
dengan mulas fungsional, H2RA dapat mengurangi sensitivitas sekuestran asam empedu. Ini telah dievaluasi sebagai terapi tambahan untuk
kemoreseptor esofagus terhadap asam pada pasien dengan pasien dengan respons suboptimal terhadap PPl dosis standar. Dalam uji
hipersensitivitas refluks, meskipun belum ada penelitian spesifik mengenai coba acak terkontrol plasebo tersamar ganda fase 2A, persentase hari bebas
efek ini. Ketika pasien dengan nyeri ulu hati fungsional yang didefinisikan sakit maag meningkat sebesar 30,3% pada pasien yang diberikan IW-3718,
oleh Rome II diobati dengan PPI dua kali sehari, hanya pasien dengan dan sebesar 34,6% pada pasien dengan refluks empedu, dibandingkan
indeks gejala positif (kelompok hipersensitivitas refluks) yang merespons dengan 24,7% dan 23,6%, masing-masing, pada pasien yang diberi plasebo.
pengobatan, yang menunjukkan peran untuk meminimalkan paparan asam
esofagus. Tidak jelas apakah terapi PPI dua kali sehari merupakan dosis MUSE (Medigus, Omer, Israel) adalah perangkat stapel endoskopi
yang stabil, seperti pada pasien GERD, atau apakah penekanan asam lebih untuk fundoplikasi anterior. Alat ini menggunakan endoskopi
lanjut dengan dosis yang lebih tinggi dapat memberikan manfaat terapeutik termodifikasi yang dilengkapi kamera mini, probe ultrasuara, dan stapler
yang lebih baik. ARS telah berhasil pada pasien yang dipilih dengan cermat di ujungnya. Beberapa penelitian jangka pendek menunjukkan
dengan hipersensitivitas refluks yang didiagnosis menggunakan kemanjuran teknik ini dalam mengurangi gejala dan meningkatkan
pemantauan impedansi pH 0,181, 182, ARS mengurangi episode refluks kualitas hidup terkait kesehatan. Perawatan ini mengurangi penggunaan
asam, asam lemah, dan cair dan campuran setelah fundoplikasi. 2 Terlepas PPI dan paparan asam esofagus.* Bahan penggembur yang dapat
dari itu, sangat sedikit penelitian yang menilai nilai pilihan invasif (ARS, disuntikkan (Impleo Medical, St Paul, MN) dimasukkan ke dalam
terapi endoskopi) pada pasien dengan hipersensitivitas refluks; nlebih jaringan submukosa LES selama endoskopi telah dinilai pada pasien
banyak data diperlukan. dengan GERD.
Suntikan tersebut menciptakan tonjolan jaringan yang secara mekanis menghambat
refluks gastroesofageal. Namun, hanya ada sedikit data yang menunjukkan
Sedangkan untuk pasien dengan mulas fungsional, pasien dengan kemanjurannya."
hipersensitivitas refluks dapat memperoleh manfaat dari neuromodulator.
Hanya ada sedikit penelitian mengenai pengobatan khusus untuk pasien ini.
Dalam uji coba acak terkontrol plasebo, pasien dengan hipersensitivitas
refluks yang diberi citalopram setiap hari (20 mg) selama 6 bulan mengalami
penurunan gejala yang signifikan dibandingkan dengan pasien yang diberi
plasebo.l83
Modalitas pengobatan alternatif, seperti akupunktur, telah
dilaporkan mengurangi mulas pada pasien yang tidak merespons terapi
PPI sekali sehari. Penelitian-penelitian ini kemungkinan besar
mencakup pasien dengan mulas fungsional dan hipersensitivitas refluks.
184 Pernapasan diafragma juga dapat melengkapi penatalaksanaan
GERD.

Arah masa depan

Pengembangan obat untuk GERD telah menurun drastis
selama dekade terakhir, terutama karena sebagian besar PPL
telah menjadi obat generik dan tersedia tanpa resep. o Sebaliknya,
terdapat peningkatan minat terhadap strategi terapi nonmedis,
terutama bagi pasien yang tidak tertarik, alergi, tidak patuh, atau
khawatir terhadap pengobatan PPI jangka panjang 187

Penghambat asam kompetitif kalium (P-CABs) menghambat pompa

proton dalam mekanisme Kt yang kompetitif namun reversibel. P-CAB
menunjukkan penghambatan sekresi asam dini yang signifikan sebagai
respons terhadap peningkatan cepat konsentrasi plasma puncak. *
Vonoprazan adalah P-CAB pertama yang melakukannya
 312 Gyawali and Fass Gastroenterology Vol. 154, No. 2

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comparative trial of a potassium-competitive acid Conflicts of interest

blocker (AZD0865) and esomeprazole for the treatment R.F. is an advisor to Ironwood, Mederi Therapeutics and Ethicon. Speaker for
AstraZeneca, Takeda and Mederi Therapeutics and receives a research grant
of patients with nonerosive reflux disease. Am J from Ironwood. C.P.G is an advisor to Torax, Ironwood, Medtronic and
Gastroenterol 2008;103:20–26. Diversatek. Speaker for Medtronic and Diversatek.