TUGAS TRANSLATE JURNAL

Hepatitis C Infection and Periodontal Disease: Is

there a Common Immunological Link?
Dorin Nicolae Gheorghe; Foia, Liliana; Toma, Vasilica; Surdu, Amelia; Herascu, Elena; et al.
Journal of Immunology Research; New York Vol. 2018, (2018). DOI:10.1155/2018/8720101

(ProQuest)

Penerjemah:

DHANU BINTANG SATRIA

NIM: J2A019018

FAKULTAS KEDOKTERAN GIGI

UNIVERSITAS MUHAMMADIYAH SEMARANG

Infeksi Hepatitis C dan Penyakit Periodontal: Adakah Tautan Imunologis yang
Umum?
Dorin Nicolae Gheorghe; Foia, Liliana; Toma, Vasilica; Surdu, Amelia; Herascu,
Elena; et al. Jurnal Penelitian Imunologi; New York Vol. 2018, (2018). DOI:
10.1155 / 2018/8720101

Infeksi virus hepatitis C (HCV) dapat berdampak penting pada status

kesehatan mulut pasien, mendukung kondisi seperti penyakit periodontal dan kanker
mulut . Tinjauan literatur ilmiah yang ada ditulis dalam bahasa Inggris dilakukan,
mencari manifestasi oral dan periodontal dari infeksi HCV dan dampaknya terhadap
cairan oral . Infeksi HCV dapat menentukan manifestasi ekstrahepatik langsung pada
tingkat oral dan periodontal termasuk oral lichen planus, sialadenitis seperti Sjögren,
dan oral.kanker. Perubahan yang disebabkan oleh infeksi pada sistem kekebalan
tubuh, pola makan, dan gaya hidup subjek dapat memfasilitasi perkembangan kondisi
mulut seperti penyakit periodontal . Perubahan penting juga terjadi pada komposisi
saliva pasien dan cairan gingiva. Pasien yang terinfeksi HCV perlu dimonitor secara
hati-hati dalam hal kesehatan mulut karena infeksi dengan virus dapat mengakibatkan
oralkomplikasi. Kekhususan seluler dan molekuler cairan gingiva pasien yang
terinfeksi HCV dapat menjawab beberapa pertanyaan mengenai dampaknya terhadap
penurunan periodonium dan apakah ini merujuk pada kemungkinan hubungan dua
arah, dengan penyesuaian biomarker hati yang diinduksi oleh status inflamasi pasien
periodontal.

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1. Pendahuluan
 Meskipun upaya-upaya penting telah dilakukan dalam beberapa tahun terakhir
untuk meningkatkan kesadaran akan kemungkinan penularan dan pengobatan, virus
hepatitis C (HCV) tetap menjadi masalah kesehatan global yang penting. Infeksi virus
yang tidak diobati menyebabkan peradangan hati kronis. Hepatitis kronis memiliki
komplikasi seperti sirosis hati dan karsinoma hepatoseluler yang berakibat fatal bagi
pasien [1, 2]. Selain itu, peristiwa patologis yang memicu infeksi HCV meluas ke luar
hati, sejumlah manifestasi ekstrahepatik termasuk cryoglobulinemia, limfoma ganas,
sindrom Sjögren, atau lichen planus oral yang telah dibahas dalam literatur [3–7].

Data terkini yang tersedia dari WHO (World Health Organization)

menunjukkan bahwa, pada 2015, lebih dari 70 juta orang terinfeksi HCV,
menghasilkan prevalensi global sekitar 1%. Infeksi HCV mempengaruhi semua
wilayah di dunia, dengan perbedaan penting antar negara. Menurut WHO, prevalensi
tertinggi infeksi HCV dilaporkan untuk wilayah Mediterania Timur dan Eropa.
Diperkirakan 1,75 juta infeksi HCV baru terjadi di seluruh dunia pada 2015 [8].
Infeksi sulit didiagnosis pada tahap awal karena tidak menunjukkan tanda-tanda
klinis yang jelas dan hanya dapat ditunjukkan melalui uji serologis. Aspek ini dapat
ditingkatkan dengan analisis yang lebih hati-hati dari manifestasi ekstrahepatik yang
hampir 75% dari pasien yang terinfeksi mengekspresikan [9]. Diyakini bahwa virus
dapat di-host di dalam jaringan ekstrahepatik, membuatnya lebih rentan terhadap
penularan dan lebih sulit untuk diobati [10]. Oleh karena itu, perkembangan
komplikasi infeksi virus seperti karsinoma hepatoseluler dapat memiliki dampak
penting pada sistem kekebalan pasien [11], membuatnya semakin sulit untuk
ditangani oleh mekanisme fisiologis defensif.

Dampak infeksi HCV pada kesehatan mulut telah menerima pendapat yang
berbeda dari waktu ke waktu, bervariasi dari bukti klinis hingga meta-analisis dan
pendekatan yang lebih luas pada subjek [12]. Gangguan kesehatan mulut untuk
pasien yang terinfeksi dapat disebabkan oleh kerusakan hati, sistem kekebalan tubuh
yang rusak, atau rendahnya dorongan pasien yang terinfeksi untuk mencari perawatan
gigi [13, 14]. Beberapa penelitian membahas pentingnya infeksi HCV pada rongga
mulut , menyoroti perubahan patologis gigi dan manifestasi ekstrahepatik lainnya
(EHMs) dengan implikasi oral [15], sementara yang lain mengungkapkan dampak
tipe A, B, dan C terhadap hepatitis C pada cairan oral. , melihat kemungkinan
pengangkutan virus hepatitis di seluruh air liur dan cairan gingiva [16]. Ulasan yang
lebih baru tentang Han et al. menunjukkan sinergi antara kondisi periodontal dan hati,
selain hepatitis virus, menguraikan dampak bersama yang mungkin diberikan oleh
inflamasi periodontal dan hepatik [17]. Artikel ulasan saat ini berfokus terutama pada
hubungan dua arah peradangan periodontal dan infeksi HCV dalam hal manifestasi
klinis, ekspresi molekul biomarker dalam cairan oral dan signifikansinya bagi praktisi
medis, baik periodontis dan hepatologis, dengan minat selanjutnya pada apakah
kehadiran peradangan periodontal dapat meningkatkan risiko penularan virus
hepatitis C melalui cairan oral , terutama cairan crevicular gingiva (GCF).

2. Infeksi HCV: Dampak pada Kesehatan Mulut dan Status Periodontal

2.1. Infeksi HCV dan Status Periodontal

Coates et al. mempelajari masalah kesehatan mulut dari orang yang terinfeksi
HCV dalam penelitian terhadap 87 pasien yang berusia antara 35 dan 44 tahun [13].
Perubahan patologis gigi, diekspresikan dengan bantuan indeks DMFT (Decayed,
Missing, Filled Teeth index), tiga kali lebih penting untuk pasien yang terinfeksi HCV
daripada kelompok kontrol untuk gigi dengan lesi karies. Pasien HCV-positif juga
menunjukkan jumlah gigi yang hilang lebih banyak tetapi memiliki lebih sedikit
tambalan gigi dibandingkan kontrol [13].

Status periodontal pasien dievaluasi menggunakan indeks CPITN

(Community Periodontal Index of Needs Needs), mencatat peningkatan perdarahan
gingiva untuk pasien yang terinfeksi dan kantong periodontal yang lebih dalam, untuk
kelompok usia berkisar antara 25-34 dan 35-44 tahun. Meskipun temuan ini tidak
signifikan secara statistik untuk jumlah subjek, kecenderungan penurunan status
periodontal telah ditunjukkan pada subjek yang terinfeksi. Para penulis menyatakan
bahwa karakteristik diet dan kekhasan sosial lainnya seperti kurangnya perawatan
gigi dan periodontal yang tepat dapat menjadi penyebab tren ini [13].

Sebuah mekanisme patologis yang mungkin yang mungkin menjelaskan

pengaruh hepatitis C kronis pada status periodontal dapat dikaitkan dengan resistensi
insulin (IR) dan pengembangan proses inflamasi kronis di hati.

Resistensi insulin adalah kondisi patologis di mana sel-sel tidak bereaksi

secara normal terhadap insulin, yang terkait erat dengan diabetes dan obesitas.
Penyakit periodontal telah dikaitkan dengan sindrom metabolik (termasuk resistensi
insulin) [18], dan hubungan antara infeksi HCV dan resistensi insulin telah divalidasi
juga [19]. Disarankan bahwa, mengingat hubungan antara peradangan kronis hati dan
resistensi insulin [19], respon inflamasi periodontal dapat dimodifikasi pada pasien
HCV dengan fibrositas hati dan obesitas [20]. Serfaty et al. menyarankan bahwa
beberapa mekanisme tampaknya terlibat dalam eksaserbasi IR dalam HCV kronis,
sindrom metabolik dan proses inflamasi kronis di antara mereka. Jalur patologis ini
meningkatkan produksi sitokin proinflamasi (terutama TNF-alpha, adiponektin, dan
IL-6) [19]. Sitokin ini terlibat baik dalam pemicu dan perkembangan penyakit
periodontal atau dalam hubungan antara penyakit periodontal dan IR [21].

Hati mengendalikan banyak aspek fisiologi sistem kekebalan tubuh mulai dari
produksi sel defensif hingga kontrol aktivitas kekebalan tubuh yang tidak spesifik
yang mengarah ke keadaan peradangan kronis. Akibatnya, gangguan fungsi hati yang
disebabkan oleh peradangan kronis menggeser seluruh kemampuan pertahanan
organisme. Perubahan tersebut dapat menarik karakteristik sel neutrofil (kepatuhan
yang lebih rendah, mobilitas, dan kemampuan fagositik) dan aktivitas sistem
komplemen yang meningkatkan reaksi pertahanan sel-sel antibodi [22]. Kolaborasi
antara sel-sel neutrofil dan sistem komplemen sangat penting untuk aktivitas normal
mekanisme defensif terhadap bakteri patogen periodontal [23].

Penyakit periodontal terjadi ketika keseimbangan ekologis rongga mulut

terganggu dan patogen bakteri periodontal mulai memicu reaksi inflamasi.
Selanjutnya, peradangan menjadi kronis dan menyebabkan pembubaran jaringan
periodontal. Mekanisme patologis penyakit dapat dipengaruhi oleh gangguan sistem
kekebalan tubuh pasien. Ini tidak hanya menyebabkan pergeseran spesies bakteri oral
tetapi juga menciptakan reaksi inflamasi yang tidak memadai [24]. Ini dapat menjadi
kasus untuk pasien yang menderita leukemia atau kanker atau bagi mereka yang
menjalani kemoterapi, serta untuk pasien dengan fungsi hati yang rusak yang
disebabkan oleh sirosis hati [25].

Kombinasi faktor internal seperti resistensi insulin, disfungsi imunologis,

status inflamasi kronis yang sedang berlangsung, dan yang eksternal termasuk
kurangnya perawatan gigi yang tepat dapat membuat pasien yang terinfeksi HCV
menghadapi risiko pengembangan penyakit periodontal . Dalam aspek ini, tidak
hanya pasien terinfeksi-HCV ragu-ragu untuk mengatasi masalah gigi mereka, tetapi
rencana dan pilihan perawatan mereka juga dapat dibatasi oleh keengganan beberapa
dokter gigi untuk merawat mereka karena risiko penyebaran infeksi [26].

2.2. EHM dengan Implikasi Oral dan Penyakit Periodontal

Sementara masalah gigi dan periodontal tampaknya merupakan konsekuensi

tidak langsung dari infeksi virus, kondisi kesehatan mulut lainnya seperti oral lichen
planus, sialadenitis seperti Sjögren, dan karsinoma sel-sel skuamosa oral secara
langsung disebabkan oleh defisiensi imun yang disebabkan oleh virus. , dengan
demikian dianggap sebagai manifestasi ekstrahepatik (EHM) dari infeksi [15, 27, 28].
Namun, mekanisme biologis melalui mana infeksi HCV dapat memicu manifestasi
ekstrahepatik oral belum sepenuhnya dijelaskan.

Lichen planus adalah kondisi kulit yang memanifestasikan dirinya dengan lesi
inflamasi. Lichen planus juga dapat melibatkan mukosa mulut , terutama lapisan
dalam pipi, dalam hal ini dinamai oral lichen planus (OLP). Berbeda dengan lokasi
kulit dari kondisi, di mana sering menghilang secara spontan, kondisi lokal khusus
rongga mulut mencegah hal ini terjadi dan bahkan dapat menimbulkan lesi untuk
mengembangkan potensi ganas [29]. Ulasan meta-analisis pada tautan antara OLP
dan infeksi HCV telah membuktikan adanya hubungan yang kuat antara keduanya
[30]. Temuan ini memiliki signifikansi klinis yang penting karena hubungan dua arah
antara kedua kondisi tersebut menarik bagi pasien yang didiagnosis dengan satu atau
lain, untuk dirujuk ke kedua spesialis. Sebuah studi oleh Azizi dan Rezaee
menunjukkan bahwa jika lesi OLP diposisikan pada gingiva, itu menghasilkan bentuk
gingivitis deskuamatif, dengan dampak negatif pada status periodontal [31]. Secara
klinis, ini diterjemahkan menjadi memburuknya indeks yang diteliti untuk pasien
OLP versus kontrol, seperti indeks plak, indeks gingiva, kedalaman probing,
perdarahan saat probing, dan kehilangan perlekatan [31]. Dampak negatif dari lesi
OLP pada status periodontal juga dikonfirmasi oleh penelitian Lopez-Jornet dan
Camacho-Alonso yang mengungkapkan peningkatan nilai rata-rata CPITN untuk
pasien OLP dibandingkan dengan kelompok kontrol yang sehat [32].

Sindrom Sjögren adalah autoimun kronis penyakit yang mempengaruhi

kelenjar sekresi tubuh, seperti air mata dan kelenjar ludah. Gangguan fungsi kelenjar
ini menghasilkan mata dan mulut kering, dengan konsekuensi negatif pada kualitas
hidup pasien. Ketika aliran saliva ke mulut berkurang atau bahkan tidak ada pada
stadium lanjut penyakit ini , seluruh rongga mulut dipengaruhi oleh berbagai
peristiwa patologis seperti yang dijelaskan oleh Fox [33]. Gigi tidak lagi terlindungi
dari bakteri oleh komponen saliva, dan plak gigi tidak lagi dihilangkan oleh aliran
saliva. Ini memicu kemajuan menuju karies gigi dan pergeseran mukosa mulut yang
menjadi lebih rapuh dan rentan terhadap trauma dan infeksi. Ketika kelenjar air liur
mencoba untuk mengimbangi kurangnya produksi air liur, mereka tumbuh dalam
ukuran dan mengubah penampilan wajah pasien. Meskipun jalur patologis sindrom
Sjögren tidak sepenuhnya digambarkan, kemungkinan sifat autoimun dari kondisi ini
dapat terkait erat dengan infeksi virus. Meskipun dampak negatif dari berkurangnya
aliran saliva pada rongga mulut , hubungan langsung antara sindrom Sjögren dan
penyakit periodontal belum terbukti. Sebuah studi oleh Kuru et al. tidak menemukan
perbedaan yang signifikan antara status periodontal pasien tersebut dan individu
sehat, dalam hal elemen klinis dan bakteri seperti analisis mikrobiologis sampel plak
dan karakteristik lesi periodontal [34]. Penelitian lain oleh Boutsi et al. menunjukkan
bahwa pasien sindrom Sjögren tanpa komorbiditas lain menyatakan status periodontal
yang tidak berbeda secara signifikan dan menunjukkan kebersihan mulut yang lebih
baik daripada subyek kontrol [35].

Oral karsinoma -squamous-sel, jenis yang paling sering lisan kanker, adalah
satu lagi infeksi HCV ekstrahepatik manifestasi. Seiring dengan elemen perilaku
seperti asupan tembakau dan alkohol, infeksi virus dianggap sebagai faktor risiko
penting untuk perkembangan kanker mulut yang sering berasal dari lesi premaligna
atau potensial ganas pada mukosa mulut seperti leukoplasia, erythroplasia, dan lichen
planus oral . Namun demikian, untuk pasien yang terinfeksi HCV, perkembangan
kanker mulut telah dilaporkan bahkan tanpa adanya lesi praligna [36]. Ulasan
sistematis oleh Javed dan Warnakulasuriya menunjukkan bahwa penyakit periodontal
dapat meningkatkan risiko kanker mulut [37]. Tetapi bahkan dengan peningkatan
yang sempit, kepentingannya bahkan lebih besar jika faktor-faktor risiko bersama
lainnya untuk kedua kondisi seperti konsumsi tembakau dan alkohol
dipertimbangkan. Selain itu, hasil penelitian oleh Narayan et al. menunjukkan bahwa
karsinoma sel skuamosa oral dan status periodontal berbanding lurus dalam aspek
klinis dan mikrobiologis [38]. Namun, penelitian lebih lanjut diperlukan untuk
mempelajari status periodontal pada pasien yang terinfeksi HCV dengan EHMs oral
karena kerumitan subjek perlu dianalisis secara cermat oleh berbagai spesialisasi
medis.

3. Penularan Infeksi HCV: Penyakit Periodontal dan Cairan Mulut

3.1. Air liur

Infeksi HCV terjadi dengan bersentuhan dengan molekul virus RNA dari
pasien yang terinfeksi. Molekul-molekul ini dibawa oleh darah pasien dan dapat
ditemukan baik di dalam produk darah (seperti transfusi darah dari donor yang belum
diuji) atau pada berbagai objek setelah kontak darah yang terinfeksi (seperti jarum
suntik) yang digunakan oleh individu yang berbeda secara bersamaan (seperti dalam
kasus ini). kelompok kecanduan narkoba). Penyebaran virus ini bahkan lebih sulit
untuk dilawan karena dapat juga ditularkan melalui kontak seksual tanpa kondom,
ketika satu pasangan terinfeksi tetapi tidak mengetahui fakta ini karena penyakit ini
tidak aktif secara klinis pada tahap pertama. Virus ini juga dapat ditularkan melalui
jarum yang tidak disterilkan dengan baik yang digunakan dalam menato dan menusuk
[8].

Virus ini memiliki limfotropisme yang kuat dan dapat ditemukan di dalam sel
darah mononuklear. Oleh karena itu, dapat dilacak dalam cairan yang mengandung
sel-sel tersebut, seperti air liur [39-43]. Selain itu, terlepas dari cara penularan
parenteral utama, infeksi HCV juga telah dilaporkan pada pasien yang tidak terpajan
jarum, transfusi darah, atau pasangan yang terinfeksi, yang mungkin menyarankan
adanya kemungkinan vektor penularan alternatif [44]. Dengan demikian, beberapa
penelitian telah menguji kemungkinan molekul RNA virus menular untuk hadir
dalam cairan tubuh lain selain darah [16, 45], prevalensi molekul tersebut dalam air
liur yang ditemukan tidak konsisten [46, 47].

Caldeira et al. melakukan penelitian di mana mereka mencatat 36,8% sampel

saliva HCV RNA positif tanpa adanya antibodi serologis anti-HCV dan 23,5% sampel
saliva RNA HCV positif bersama dengan antibodi serologis anti-HCV yang ada,
semua sampel berasal dari pasien yang terinfeksi [48]. Namun demikian, karena fakta
bahwa HCV membutuhkan sel inang untuk bereplikasi di dalamnya (menargetkan
hepatosit dan sel darah perifer), tingkat identifikasi RNA virus dalam air liur
bervariasi hingga tingkat yang signifikan, karena variabilitas kehadiran molekul virus
di perifer. sel-sel darah yang ditemukan dalam air liur dapat memiliki dampak penting
pada hasil deteksi [49-53]. Proses replikasi RNA virus membutuhkan pembuatan
RNA perantara yang negatif. Sementara beberapa penelitian tidak menemukan trans
dari RNA untai negatif dalam sampel saliva [54], tipe RNA ini ditemukan dalam
sampel jaringan kelenjar saliva pasien yang terinfeksi juga menderita sialadenitis
[55].

Sejauh ini mekanisme biologis yang memungkinkan virus ada dalam air liur
tidak jelas. Meskipun virus ini terutama dianggap hepatotropik, ada hasil ilmiah yang
menunjukkan bahwa replikasinya juga dapat terjadi di dalam sel darah mononuklear
perifer yang ditemukan di kelenjar ludah submandibular. Fakta ini didukung oleh
keterlibatan virus dalam pengembangan kondisi seperti sialadenitis dan sindrom
Sjögren [56]. Arrieta et al. melakukan penelitian in situ pada sel epitel kelenjar ludah
yang berasal dari pasien yang terinfeksi HCV dan menderita sialadenitis atau sindrom
Sjögren. Hasil penelitian melaporkan prevalensi sel yang terinfeksi HCV dalam air
liur berkisar antara 25% dan 48,8% [55].

Probabilitas air liur menjadi vektor untuk infeksi HCV juga telah dibahas
dalam beberapa studi kasus, menangani keduanya, laporan klinis pasien yang
sebelumnya telah digigit oleh orang HCV yang terinfeksi, dan penelitian
eksperimental [57, 58]. Namun, penelitian yang menggunakan metode polymerase
chain reaction (PCR) dan mencoba mendeteksi salinan viral load dalam sampel air
liur belum membuktikan potensi infeksi dari salinan virus ini, prevalensi viral load
virus menjadi sangat berbeda [59, 60].

Hasil penelitian yang tidak konsisten menargetkan deteksi RNA virus dalam
air liur pasien yang terinfeksi HCV dapat dijelaskan melalui asal virus sebagai cairan
crevikular gingiva, lebih tepatnya sel darah mononuklear yang ditemukan dalam
cairan ini. Oleh karena itu, status periodontal dapat dianggap sebagai faktor yang
berkontribusi terhadap keberadaan HCV dalam air liur [61]. Sedangkan aspartat
transaminase (AST) tingkat ludah telah mencatat tingkat signifikan lebih tinggi pada
sampel dari pasien dengan periodontal kronis penyakit dan nilai-nilai AST berkorelasi
dengan tingkat cedera jaringan periodontal [62], molekul RNA virus telah ditemukan
di sampel air liur dari HCV pasien terlepas dari status periodontal mereka [63].

3.2. Cairan Crevicular Gingiva

 Potensi antigen dan antibodi HCV untuk hadir dalam GCF juga telah
dipelajari. GCF adalah cairan oral tertentu , karena meskipun berasal dari lingkungan
internal (dari serum), cairan ini dikeluarkan di ruang luar tubuh (sulkus gingiva) dan
semakin jauh ke dalam rongga mulut terbuka . Dengan demikian, kekhasannya dalam
komposisi (penanda inflamasi) dan perilaku (peningkatan aliran selama inflamasi)
menjadikan GCF subjek yang layak untuk diteliti tentang masalah hubungan dua arah
antara penyakit periodontal dan infeksi HCV. Cairan mengandung komponen plak
bakteri, sel-sel inflamasi sistem kekebalan tubuh, jejak jaringan ikat, dan faktor serum
lainnya [64].

RNA virus dan antibodi anti-HCV telah terdeteksi dalam sampel GCF yang
dikumpulkan dari pasien yang terinfeksi HCV [65-67]. Molekul virus dapat
diturunkan menjadi air liur, sehingga menjadikan GCF sumber kontaminasi air liur
pasien yang terinfeksi HCV.

Peradangan periodontal, dalam bentuk gingivitis atau periodontitis,

menyebabkan peningkatan aliran cairan crevikular gingiva dan perdarahan gingiva
yang lebih sering. Akibatnya, virus dapat bermigrasi dengan lebih mudah dari aliran
darah ke cairan crevicular gingiva dan semakin jauh ke dalam air liur, karena ia
dibawa oleh sel darah mononuklear perifer [68]. Satu studi menemukan prevalensi
59% untuk RNA HCV dalam GCF pasien yang terinfeksi HCV [67]. Hasil penelitian
lain menunjukkan tingkat prevalensi 83,72% untuk antibodi anti-HCV dalam cairan
gingiva pasien yang terinfeksi, setelah menggunakan tes deteksi cepat [69]. Suzuki et
al. menunjukkan bahwa konsentrasi HCV RNA yang lebih tinggi ditemukan dalam
GCF daripada dalam air liur untuk 77% dari pasien yang terinfeksi yang terdaftar
dalam penelitian ini, sementara pada 78% kasus, materi genetik virus ditemukan
dalam GCF bahkan jika tidak ada. dalam air liur pasien yang terinfeksi [68]. Teori
bahwa sumber HCV RNA dan antibodi dalam rongga mulut sebenarnya adalah cairan
crevicular gingiva juga didukung oleh penelitian Montebugnoli dan Dolci [65].
Namun demikian, efisiensi penularan virus melalui cairan oral dapat tergantung pada
viral load, yang berarti bahwa penelitian kuantitatif lebih lanjut diperlukan untuk
menilai risiko potensial cara infeksi nonparenteral dengan HCV.

Sejauh data ilmiah saat ini berjalan, tampak bahwa jawaban terbaik untuk
keberadaan molekul RNA HCV dalam cairan gingiva mengacu pada leukosit yang
terinfeksi [70] yang mengandung strain virus dan ditransfer dari aliran darah ke
cairan gingiva, terutama di kasus peradangan gingiva. Dengan demikian, subjek
masih memerlukan penelitian lebih lanjut yang harus fokus pada kekhususan
komponen, baik seluler dan molekuler, cairan gingiva pasien yang terinfeksi HCV.

3.3. Implikasi Kehadiran RNA Viral dalam Cairan Oral

Deteksi molekul RNA HCV dalam cairan tubuh manusia selain darah dapat
dipengaruhi oleh pengambilan sampel dan metode analisis. Pengujian sampel air liur
untuk antigen atau antibodi telah mengungkapkan spesifisitas yang sama atau bahkan
lebih tinggi dibandingkan dengan pengujian serum, seperti yang disarankan oleh
penelitian yang menilai efisiensi alat diagnosis standar untuk infeksi HCV dan yang
lebih baru seperti kit deteksi oral RNA HCV untuk air liur, sementara juga
menawarkan cara di mana metode yang kurang invasif ini dapat ditingkatkan [66,
71]. Metode investigasi yang paling sering termasuk penggunaan uji ELISA (enzyme-
linked immunosorbent assay) untuk deteksi antibodi anti-HCV dalam serum [72].
Sebaliknya, air liur lebih mudah untuk sampel, suatu aspek yang dapat memfasilitasi
dan meningkatkan skrining pasien yang mungkin terinfeksi, sehingga memiliki
dampak pada faktor klinis, ekonomi, dan epidemiologis yang mengatasi masalah
infeksi HCV [71]. Namun, bahkan jika dalam hal spesifisitas kedua cairan tersebut
sebanding, dalam hal sensibilitas, tes yang digunakan pada serum darah lebih tepat
karena terdapat konsentrasi antibodi yang lebih rendah dalam air liur. Penurunan ini
dapat ditingkatkan dengan penyesuaian protokol seperti ekspansi sampel,
pengurangan dilusi, dan augmentasi waktu inkubasi [66]. De Cock et al.
menunjukkan bahwa metode ELISA yang dimodifikasi dapat digunakan sebagai alat
untuk menjalankan studi epidemiologi untuk deteksi antibodi anti-HCV dalam cairan
oral , karena menunjukkan tingkat spesifisitas yang memuaskan [73].

Ada penelitian [74, 75] yang mengklaim sensitivitas 80-87% dan spesifisitas
100% untuk deteksi antibodi anti-HCV dalam cairan oral dibandingkan dengan 100%
untuk serum darah. Meskipun tidak ada korelasi yang signifikan antara viral load dan
tingkat HCV dalam saliva, pasien dengan kadar HCV serum yang rendah
menunjukkan konsentrasi viral load RNA yang kecil dalam saliva. Namun demikian,
Hermida et al. mengidentifikasi korelasi yang signifikan antara viremia serum dan
konsentrasi viral load dalam saliva [76]. Ini mungkin memiliki dampak penting di
antara pengasuh, menunjukkan perlunya penelitian epidemiologi lebih lanjut [65].
Namun, data tersebut masih kontroversial, karena beberapa penulis mengungkapkan
bahwa keberadaan viral load RNA dalam saliva tidak tergantung pada viremia serum
atau adanya kondisi oral lainnya [77].

Keterlibatan HCV dengan sendirinya dalam disfungsi saliva masih

dipertanyakan [78, 79], tetapi hubungan infeksi hepatitis C dengan sindrom Sjögren
diakui sebagai penyebab hipofungsi saliva, penurunan laju aliran saliva yang
berpotensi menjadi penyebab sebagian besar gigi. dan kondisi oral pada pasien yang
terinfeksi HCV, serta resistensi insulin yang dimanifestasikan pasien ini, sehingga
rentan terhadap perkembangan penyakit periodontal . Manajemen pasien yang
terinfeksi HCV adalah tantangan nyata karena kekhasan patologis yang disiratkan
oleh pasien ini dan dampak infeksi pada perencanaan perawatan dan prognostik.

4. Penyakit Periodontal : Dampak pada Infeksi HCV

Fungsi hati terutama dievaluasi dengan pengujian serologis dua enzim —

aspartate aminotransferase (AST) dan alanine aminotransferase (ALT), levelnya
meningkat dalam tekanan hati dan peradangan. Tingkat AST ludah telah mencatat
tingkat signifikan lebih tinggi pada sampel dari pasien dengan periodontal kronis
penyakit seperti yang ditunjukkan dalam studi oleh Kudva et al., Dan apa yang lebih,
nilai-nilai ludah AST berkorelasi dengan tingkat cedera jaringan periodontal [62].
 GCF mewakili transudat serosa atau eksudat inflamasi, tergantung pada status
jaringan periodontal dan dapat dengan mudah dikumpulkan dari sulkus gingiva yang
mengelilingi setiap gigi. Berbagai komponen GCF, seperti sitokin dan
metalloproteinase (MMPs), seperti IL-1, IL-6, IL-12, TNF-alpha, VEGF, dan MMP9
dapat dianggap sebagai penanda inflamasi periodontal, identifikasi mereka dalam
GCF yang digunakan untuk mempelajari jalur umum antara penyakit periodontal dan
kondisi lain seperti diabetes tipe 1 dan 2, penyakit jantung , dan rheumatoid arthritis
[80-82], karena keberadaan beberapa biomarker ini telah terdeteksi dalam serum dan
epitel gingiva pada periodontal. pasien yang terpengaruh dengan beberapa
komorbiditas [82-85].

Data ilmiah membenarkan perlunya penelitian menilai berbagai komponen

proinflamasi GCF pada pasien dengan infeksi HCV atau dengan infeksi HCV dan
penyakit periodontal . Namun, ada penelitian yang menemukan tingkat tinggi dari
beberapa penanda ini seperti interleukin IL-1, IL-6 dan interferon IFN-gamma dalam
serum pasien yang terinfeksi HCV dan juga dalam serum dan GCF pasien dengan
infeksi periodontal [86 –88]. Penelitian lebih lanjut diperlukan untuk menilai
hubungan antara penanda inflamasi lain yang ditemukan dalam cairan gingiva dan
infeksi HCV [20] dan dengan demikian untuk menyelidiki apakah pasien yang
terinfeksi HCV akan memiliki risiko lebih tinggi untuk mengembangkan cedera
periodontal atau jika pasien yang mengalami kompromi periodontal dengan hepatitis
C tipe bisa memiliki ekspresi yang lebih tinggi dari biomarker spesifik hati lainnya,
bersama dengan beberapa wawasan tentang mekanisme yang mendasarinya.

Itu menunjukkan bahwa tingkat AST dalam GCF pasien dengan penyakit
periodontal meningkat dan berkorelasi dengan aktivitas penyakit periodontal [89, 90],
mencatat tren penurunan setelah perawatan periodontal dan mengaitkan peningkatan
parameter klinis [91]. Selain itu, dalam mata pelajaran penyakit hati berlemak
nonalkohol (NAFLD), ada peningkatan biomarker hati yang penting (dinyatakan
sebagai aktivitas ALT dan AST) setelah terapi periodontal yang efisien. Dengan
demikian, radang periodontal ditentukan oleh P . gingivalis pada pasien NAFLD bisa
menjadi faktor risiko untuk eksaserbasi NAFLD, dan perawatan periodontal dapat
berguna dalam pengelolaan subjek NAFLD [92]. Mekanisme yang dianggap
bertanggung jawab atas implikasi periodontitis pada penyakit hati yang berbeda
terkait dengan agen bakteri, mediator proinflamasi, dan stres oksidatif. Bersama
dengan sitokin dan kemokin, molekul lain seperti heat shock protein (HSPs) dapat
diproduksi sebagai hasil dari agresi bakteri periodontal dan akibatnya dapat memicu
peradangan hati [17]. Bersama-sama dengan mekanisme patologis yang diusulkan
dalam Bagian 2.1 dari artikel tinjauan ini (keterlibatan IR), studi TNF-alpha dan
sitokin proinflamasi lainnya dapat memberikan penjelasan menyeluruh untuk
kemungkinan infeksi hepatitis C kronis dan koneksi penyakit periodontal .
Pemahaman yang komprehensif tentang mekanisme patologis dua arah yang
menggabungkan kedua kondisi diperlukan dalam bidang periodontologi dan
hepatologi untuk menyediakan protokol diagnostik dan perawatan yang tepat.

5. Kesimpulan

Melalui cara yang berbeda, infeksi HCV menyebabkan penurunan kesehatan

mulut pasien yang terinfeksi. Apakah dianggap oleh beberapa penulis untuk
dihubungkan dengan manifestasi infeksi ekstrahepatik atau berasal dari implikasi
sistemik (kerusakan sistem kekebalan) atau disebabkan oleh perilaku pasien
( kebersihan mulut dan pola makan yang buruk), kerusakan periodontal pada pasien
yang terinfeksi HCV menyumbang penurunan penting kualitas hidup dan
kesejahteraan. Selain itu, molekul dan antibodi RNA virus telah diidentifikasi dalam
air liur dan cairan gingiva pasien, menimbulkan pertanyaan lebih lanjut tentang
transmisi dan deteksi penyakit .

Studi tentang hubungan imunologis umum antara hepatitis C tipe C dan

kesehatan periodontal dapat menjadi subjek penelitian lebih lanjut, tidak hanya dalam
hal yang menyangkut parameter klinis tetapi juga melalui identifikasi penanda
spesifik dalam GCF, mengeksplorasi penggabungan mekanisme patologis, mungkin
terkait dengan IR dan proses inflamasi kronis. Ini mungkin mengarah pada
pemahaman yang lebih baik tentang apakah hubungan ini dua arah dan secara implisit
pada mekanisme yang mendasari yang mendorong perkembangan menuju patologi
mereka. Hubungan dua arah antara penyakit periodontal dan infeksi HCV ini
memiliki implikasi yang luas bagi pasien dan praktisi medis, baik periodontologis
atau hepatologis.

Hepatitis C Infection and Periodontal Disease: Is there a Common

Immunological Link?

Dorin Nicolae Gheorghe; Foia, Liliana; Toma, Vasilica; Surdu, Amelia;

Herascu, Elena; et al. Journal of Immunology Research; New York Vol. 2018,
(2018). DOI:10.1155/2018/8720101

Hepatitis C virus (HCV) infections could have an important impact on the oral
health status of patients, favoring conditions such as periodontal disease and oral
cancer. The review of the existing scientific literature written in English was
performed, searching for oral and periodontal manifestations of HCV infection and its
impact on the oral fluids. HCV infection can determine direct extrahepatic
manifestations at the oral and periodontal level including oral lichen planus, Sjögren-
like sialadenitis, and oral cancer. The changes caused by the infection in the subjects’
immune system, diet, and lifestyle can facilitate the development of oral conditions
such as periodontal disease. Important changes also occur in the composition of the
infected patients’ saliva and gingival fluid. HCV-infected patients need to be carefully
monitored in terms of oral health since the infection with the virus can result in oral
complications. The cellular and molecular particularities of the gingival fluid of
HCV-infected patients can answer some questions regarding its impact upon
periodontium impairment and whether this refers to a possible bidirectional
relationship, with hepatic biomarker adjustments being induced by the periodontal
patients’ inflammatory status.

This is an open access article distributed under the Creative Commons

Attribution License, which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

1. Introduction

Despite important efforts being made in the past years to raise awareness over
transmission and treatment possibilities, hepatitis C virus (HCV) remains an
important global health issue. The untreated viral infection leads to chronic
inflammation of the liver. Chronic hepatitis has complications such as hepatic
cirrhosis and hepatocellular carcinoma that are fatal for the patient [1, 2]. Moreover,
the pathological events that HCV infection triggers expand beyond the liver, a
number of extrahepatic manifestations including cryoglobulinemia, malignant
lymphoma, Sjögren syndrome, or oral lichen planus having been already discussed in
the literature [3–7].

Current data available from the WHO (World Health Organization) shows
that, in 2015, more than 70 million people were HCV infected, resulting in a global
prevalence of about 1%. The HCV infection affects all regions of the world, with
important differences between countries. According to the WHO, the highest
prevalence of HCV infection was reported for Eastern Mediterranean and European
regions. An estimated 1.75 million new HCV infections occurred worldwide in 2015
[8]. The infection is difficult to diagnose in its early stages since it does not exhibit
obvious clinical signs and can only be pinpointed through serological test. This aspect
can be improved with a more careful analysis of extrahepatic manifestations that
almost 75% of the infected patients express [9]. It is believed that the virus can be
hosted inside extrahepatic tissues, making it more prone to transmission and more
difficult to treat [10]. Hence, the development of viral infection complications such as
hepatocellular carcinoma can have a critical impact on the patient’s immune system
[11], making it even more difficult to be tackled by the defensive physiological
mechanisms.

The impact of HCV infection on oral health has received different opinions
over time, varying from clinical evidence to meta-analysis and further wider approach
on the subject [12]. Oral health impairment for the infected patients could be the
result of liver malfunction, a damaged immune system, or the low drive of the
infected patients to seek dental care [13, 14]. Several studies address the significance
of HCV infection on the oral cavity, highlighting both the dental pathological changes
and other extrahepatic manifestations (EHMs) with oral implications [15], while
others reveal the impact type A, B, and C hepatitis has on oral fluids, spotting the
possible carriage of the hepatitis viruses in the whole saliva and gingival fluid [16]. A
more recent review of Han et al. points out the synergy between periodontal and liver
conditions, other than viral hepatitis, outlining the possible joint impact that
periodontal and hepatic inflammation could provide [17]. The present review article
focuses mainly on the bidirectional relationship of periodontal inflammation and
HCV infection in terms of clinical manifestations, the molecular expression of
biomarkers within oral fluids and its significance for medical practitioners, both
periodontists and hepatologists, with a subsequent interest upon whether the presence
of periodontal inflammation could enhance the risk of hepatitis C virus transmission
through the oral fluids, especially the gingival crevicular fluid (GCF).

2. HCV Infection: Impact on Oral Health and Periodontal Status

2.1. HCV Infection and Periodontal Status

Coates et al. studied the oral health issues of HCV-infected persons in a study
upon 87 patients ageing between 35 and 44 yo [13]. The dental pathological changes,
expressed with the help of the DMFT index (Decayed, Missing, Filled Teeth index),
were three times more important for HCV-infected patients than for the control group
for teeth with carious lesions. HCV-positive patients also expressed a larger number
of missing teeth but had less dental fillings than the control [13].

The periodontal status of the patients was evaluated using the CPITN index
(Community Periodontal Index of Treatment Needs), recording increased gingival
bleeding for infected patients and deeper periodontal pockets, for the age groups
ranging between 25–34 and 35–44 years. Even though the findings were not
statistically significant for the number of subjects, a trend for impaired periodontal
status has been pointed out in infected subjects. The authors state that diet
characteristics and other social particularities such as lack of proper dental and
periodontal treatment could be the cause of this trend [13].

A possible pathological mechanism that might shed some light upon the
influence of chronic hepatitis C on periodontal status could be linked to insulin
resistance (IR) and the development of a chronic inflammatory process in the liver.

Insulin resistance is a pathological condition in which cells do not react

normally to insulin, being closely related to diabetes and obesity. Periodontal disease
has been associated with the metabolic syndrome (including insulin resistance) [18],
and a connection between HCV infection and insulin resistance has been validated as
well [19]. It was suggested that, given the association between hepatic chronic
inflammation and insulin resistance [19], the periodontal inflammatory response
could be possibly modified in HCV patients with liver fibrosity and obesity [20].
Serfaty et al. suggested that multiple mechanisms seem to be involved in IR
exacerbation in chronic HCV, the metabolic syndrome and chronic inflammatory
processes being amongst them. These pathological pathways boost proinflammatory
cytokines production (mainly TNF-alpha, adiponectin, and IL-6) [19]. These
cytokines are involved either in periodontal disease triggering and progression or in
the connection between periodontal disease and IR [21].

The liver controls many aspects of the immune system’s physiology from
defensive cell production to the control of the body’s nonspecific immune activity
leading to a chronic inflammatory state. As a result, the impaired hepatic function
caused by chronic inflammation shifts the entire defensive abilities of the organism.
Such changes can interest neutrophil cell characteristics (lower adherence, mobility,
and phagocytic abilities) and the activity of the complement system which enhances
the antibody-cell defensive reaction [22]. The collaboration between neutrophil cells
and the complement system is extremely important for the normal activity of the
defensive mechanisms against periodontal pathogenic bacteria [23].

Periodontal disease occurs when the ecological balance of the oral cavity is
disrupted and periodontal bacterial pathogens start triggering an inflammatory
reaction. Subsequently, the inflammation becomes chronic and causes the periodontal
tissues’ dissolution. The pathological mechanism of the disease can be influenced by
impairment of the patient’s immune system. This not only causes a shift in oral
bacterial species but it also creates an inadequate inflammatory reaction [24]. This
can be the case for patients suffering from leukemia or cancer or for those undergoing
chemotherapy, as well as for patients with damaged liver function caused by liver
cirrhosis [25].

The combination of internal factors such as insulin resistance, immunological

dysfunction, ongoing chronic inflammatory status, and external ones including the
lack of proper dental care could make the HCV-infected patients face the risk of
periodontal disease development. In this aspect, not only do HCV-infected patients
hesitate to address their dental issues but their treatment plan and options can also be
limited by the unwillingness of some dentists to treat them due to the risk of infection
spreading [26].

2.2. EHMs with Oral Implications and Periodontal Disease

While the dental and periodontal issues seem to be an indirect consequence of

the viral infection, other oral health conditions such as oral lichen planus, Sjögren-
like sialadenitis, and oral-squamous-cell carcinoma are directly caused by the
immune deficiency caused by the virus, thus being considered extrahepatic
manifestations (EHM) of the infection [15, 27, 28]. However, the biological
mechanism through which the HCV infection could trigger oral extrahepatic
manifestations has not yet been fully elucidated.

Lichen planus is a skin condition which manifests itself with inflammatory

lesions. Lichen planus can also involve the oral mucosa, especially the interior lining
of the cheeks, in this case being named oral lichen planus (OLP). In contrast to the
skin location of the condition, where it often disappears spontaneously, the special
local conditions of the oral cavity prevent this from happening and can even elicit the
lesion to develop a malignant potential [29]. Meta-analyses reviews on the link
between OLP and HCV infection have proven the existence of a strong connection
between the two [30]. These findings have important clinical significance as the
bidirectional connection between the two conditions is of interest for patients
diagnosed with one or another, in order to be referred to both specialists. A study by
Azizi and Rezaee showed that if the OLP lesion is positioned on the gingiva, it
produces a form of desquamative gingivitis, with a negative impact on the periodontal
status [31]. Clinically, this translates into a worsening of the studied indexes for the
OLP patients versus the control, such as plaque index, gingival index, probing depth,
bleeding on probing, and attachment loss [31]. The negative impact of OLP lesions on
the periodontal status is also confirmed by a study of Lopez-Jornet and Camacho-
Alonso that revealed elevated CPITN mean values for OLP patients compared to the
healthy control group [32].

Sjögren’s syndrome is a chronic autoimmune disease which affects the

secretory glands of the body, such as lachrymal and salivary glands. The impaired
function of these glands results in dried eyes and mouth, with negative consequences
on the patient’s life quality. As the saliva flow into the mouth is decreased or even
absent in more advanced stages of the disease, the entire oral cavity is affected by
different pathological events as described by Fox [33]. The teeth are no longer
protected against bacteria by salivary components, and the dental plaque is no longer
removed by the saliva flow. This triggers the progress toward dental caries and a shift
in the oral mucosa which becomes more fragile and vulnerable to trauma and
infection. As the salivary glands try to compensate for the lack of saliva production,
they grow in size and distort the patient’s facial appearance. Even though the
pathological pathways of Sjögren’s syndrome are not fully depicted, the possible
autoimmune nature of the condition can be closely linked to viral infection. Despite
the negative impact of the reduced salivary flow on the oral cavity, a direct
connection between Sjögren’s syndrome and periodontal disease has not yet been
proven. A study by Kuru et al. found no significant differences between the
periodontal status of such patients and healthy individuals, in terms of clinical and
bacterial elements such as plaque sample microbiological analysis and characteristics
of the periodontal lesions [34]. Another study by Boutsi et al. pointed that Sjögren’s
syndrome’s patients with no other comorbidities expressed a periodontal status that
was not significantly different and displayed even better oral hygiene than control
subjects [35].

Oral-squamous-cell carcinoma, the most frequent type of oral cancer, is

another HCV infection extrahepatic manifestation. Along with behavioral elements
such as tobacco and alcohol intake, viral infection is considered an important risk
factor for the development of oral cancer that is often derived from premalignant or
potential malignant lesions of the oral mucosa such as leukoplasia, erythroplasia, and
oral lichen planus. Nevertheless, for HCV-infected patients, the development of oral
cancer has been reported even in the absence of such premalignant lesions [36]. A
systematic review by Javed and Warnakulasuriya suggests that periodontal disease
can boost the risk for oral cancer [37]. But even with a narrow increase, the
importance is even greater if other mutual risk factors for both conditions such as
tobacco and alcohol consumption are taken into consideration. In addition, the results
of a study by Narayan et al. showed that oral-squamous-cell carcinoma and
periodontal status are directly proportional in both clinical and microbiological
aspects [38]. However, further research is required studying the periodontal status in
HCV-infected patients with oral EHMs as the complexity of the subject needs to be
closely analyzed by various medical specialties.

3. HCV Infection Transmission: Periodontal Disease and Oral Fluids

3.1. Saliva

HCV infection occurs by coming into contact with RNA viral molecules of
infected patients. These molecules are carried by the patient’s blood and can be found
either inside blood products (like blood transfusions from untested donors) or on
various objects after infected blood contact (like syringe needles) which are used by
different individuals all together (like in the case of drug-addicted groups). The
spread of the virus is even more difficult to combat as it can also be transmitted
through unprotected sexual contacts, when one partner is infected but unaware of this
fact because the disease is not clinically active in its first stages. The virus can also be
transmitted through poorly sterilized needles used in tattooing and piercing [8].

The virus has a strong lymphotropism and can be found inside mononuclear
blood cells. Therefore, it can be traced in fluids that contain such cells, like saliva
[39–43]. In addition, despite the main parenteral way of transmission, HCV infection
has also been reported in patients who were not exposed to needles, blood
transfusions, or infected partners, which may suggest the existence of possible
alternative transmission vectors [44]. As such, some studies have tested the possibility
of infectious viral RNA molecules to be present in other body fluids than the blood
[16, 45], the prevalence of such molecules in saliva being found inconsistent [46, 47].

Caldeira et al. conducted a study in which they recorded 36.8% positive HCV
RNA saliva samples in the absence of anti-HCV serological antibodies and 23.5%
positive HCV RNA saliva samples along with existent anti-HCV serological
antibodies, all samples originating from infected patients [48]. Nevertheless, due to
the fact that the HCV requires a host cell to replicate inside (targeting both
hepatocytes and peripheral blood cells), the rates of viral RNA identification in saliva
varied to a significant degree, as the variability of viral molecules’ presence in
peripheral blood cells found in saliva can have an important impact on the detection
results [49–53]. The replication process of viral RNA requires the creation of
negative-stranded intermediate RNA. While some studies have found no trances of
such negative-stranded RNA in saliva samples [54], this type of RNA was found in
the salivary gland tissue samples of infected patients also suffering from sialadenitis
[55].

The biological mechanisms which enable the virus to exist in saliva are so far
unclear. Even though the virus is mainly considered to be hepatotropic, there are
scientific results suggesting that its replication could also take place inside peripheral
mononuclear blood cells found in the submandibular salivary glands. This fact is
supported by the involvement of the virus in the development of conditions such as
sialadenitis and Sjögren’s syndrome [56]. Arrieta et al. conducted an in situ study on
salivary glands’ epithelial cells originating from patients infected with HCV and
suffering from sialadenitis or Sjögren syndrome. The results of the research reported
a prevalence of HCV-infected cells in saliva ranging between 25% and 48.8% [55].

The probability of saliva being a vector for HCV infections has also been
discussed in several case studies, addressing both, clinical reports of patients that had
previously been bitten by infected HCV persons, and experimental research [57, 58].
However, studies using the polymerase chain reaction (PCR) method and trying to
detect copies of viral RNA in saliva samples have not proven the infectious potential
of these viral copies, the prevalence of viral RNA being extremely different [59, 60].

The inconsistent results of studies targeting the detection of viral RNA in

HCV-infected patients’ saliva can be explained through the origin of the virus as
being the gingival crevicular fluid, more exactly the mononuclear blood cells found in
this fluid. Therefore, periodontal status might be considered a contributing factor for
the presence of HCV in saliva [61]. While the aspartate transaminase (AST) salivary
levels have recorded significantly higher levels in samples from patients with chronic
periodontal disease and the values of AST correlate to the degree of periodontal tissue
injury [62], viral RNA molecules have been found in saliva samples of HCV patients
regardless of their periodontal status [63].

3.2. Gingival Crevicular Fluid

The potential of HCV antigens and antibodies to be present in GCF has also
been studied. The GCF is a particular oral liquid, as despite being derived from the
internal environment (from serum) it is secreted in an outside space of the body (the
gingival sulcus) and further away into the open oral cavity. Thus, its particularities in
composition (inflammatory markers) and behavior (flow increase during
inflammation) make the GCF a study-worthy subject on the matter of bidirectional
links between periodontal disease and HCV infection. The fluid contains bacterial
plaque components, inflammatory cells of the immune system, traces of connective
tissue, and other serum factors [64].

Viral RNA and anti-HCV antibodies have been detected in GCF samples
collected from HCV-infected patients [65–67]. The viral molecules are able to pass
down into saliva, thus making the GCF the source of contamination of HCV-infected
patients’ saliva.
 Periodontal inflammation, under the form of either gingivitis or periodontitis,
causes a rise in gingival crevicular fluid flow and more frequent gingival bleeding. As
a result, the virus can migrate more easily from the bloodstream into the gingival
crevicular fluid and further away into the saliva, as it is being carried by peripheral
mononuclear blood cells [68]. One study found a prevalence of 59% for HCV RNA in
the GCF of HCV-infected patients [67]. Another study’s results pointed an 83.72%
prevalence rate for anti-HCV antibodies in the gingival fluid of infected patients, after
using a quick-detection test [69]. Suzuki et al. showed that higher concentrations of
HCV RNA were found in the GCF rather than in saliva for 77% of the infected
patients enrolled in the study, while in 78% of the cases, the viral genetic material
was found in the GCF even if it was absent in the saliva of infected patients [68]. The
theory that the source for HCV RNA and antibodies in the oral cavity is in fact the
gingival crevicular fluid is also sustained by Montebugnoli and Dolci’s research [65].
Nevertheless, the efficiency of viral transmission via oral fluids could be dependent
on the viral load, meaning that quantitative studies are further needed in order to
assess the potential risk of nonparenteral ways of infection with HCV.

As far as the current scientific data goes, it appears that the best answer to the
presence of RNA HCV molecules in the gingival fluid refers to infected leukocytes
[70] that contain viral strains and get transferred from the bloodstream into the
gingival fluid, mainly in the case of gingival inflammation. Thus, the subject still
requires further research that should focus on the component particularities, both
cellular and molecular, of HCV-infected patients’ gingival fluid.

3.3. Implications of Viral RNA Presence in Oral Fluids

The detection of HCV RNA molecules in human body fluids other than the
blood is subject to influence by sampling and analysis methods. Testing saliva
samples for antigens or antibodies has revealed a similar or even higher specificity in
comparison to testing serum, as suggested by studies assessing the efficiency of
standard diagnosis tools for HCV infection and more recent ones such as HCV RNA
oral detection kits for saliva, while also offering ways in which this less invasive
method could be improved [66, 71]. The most frequent investigation methods include
the use of the ELISA (enzyme-linked immunosorbent assay) test for the detection of
anti-HCV antibodies in serum [72]. In contrast, saliva is easier to sample, an aspect
which can facilitate and improve the screening of possible infected patients, thus
having an impact on clinical, economic, and epidemiologic factors addressing the
issue of HCV infection [71]. However, even if in terms of specificity the two fluids
are comparable, in terms of sensibility, the tests used on blood serum are more
appropriate as there is a lower concentration of antibodies in saliva. This downturn
can be improved by adjustment of the protocol such as sample expansions, dilution
reductions, and incubation time augmentation [66]. De Cock et al. showed that a
modified ELISA method can be used as a tool for running epidemiologic studies for
anti-HCV antibody detection within oral fluids, as it exhibits a satisfactory degree of
specificity [73].

There are studies [74, 75] claiming an 80–87% sensitivity and a 100%
specificity for the detection of anti-HCV antibodies in oral fluids in comparison
to100% for blood serum. Although there is no significant correlation between the
viral load and the levels of the HCV in the saliva, patients with low levels of serum
HCV pointed out a minor viral RNA concentration in the saliva. Nevertheless,
Hermida et al. identified a significant correlation between the serum viremia and the
concentration of viral RNA in saliva [76]. This may have an important impact among
caregivers, suggesting the need of further epidemiologic studies [65]. However, the
data is still controversial, as some authors revealed that the presence of viral RNA in
the saliva is not dependent on serum viremia or the presence of other oral conditions
[77].

The involvement of HCV by itself in salivary dysfunction is still questionable

[78, 79], but the association of hepatitis C infection with Sjögren’s syndrome is
recognized as a cause for salivary hypofunction, the reduced rate of salivary flow
potentially being the cause of most dental and oral conditions in patients infected with
HCV, as well as the insulin resistance which these patients manifest, thus being prone
to the development of periodontal disease. The management of HCV-infected patients
is a real challenge due to the pathological particularities that these patients imply and
to the impact that the infection has on treatment planning and prognostic.

4. Periodontal Disease: Impact on HCV Infection

The liver function is mainly evaluated by means of serological testing of two

enzymes—aspartate aminotransferase (AST) and alanine aminotransferase (ALT),
their levels being elevated in hepatic distress and inflammation. The AST salivary
levels have recorded significantly higher levels in samples from patients with chronic
periodontal disease as shown in a study by Kudva et al., and what is more, the values
of salivary AST correlate to the degree of periodontal tissue injury [62].

The GCF represents either a serous transudate or an inflammatory exudate,

depending on the status of the periodontal tissues and can easily be collected from the
gingival sulcus surrounding each tooth. Various components of the GCF, such as
cytokines and metalloproteinases (MMPs), like IL-1, IL-6, IL-12, TNF-alpha, VEGF,
and MMP9 can be considered periodontal inflammatory markers, their identification
in the GCF being used to study the common pathways between periodontal disease
and other conditions such as type 1 and 2 diabetes, heart disease, and rheumatoid
arthritis [80–82], since the presence of several of these biomarkers has been detected
in serum and gingival epithelium of the periodontal-affected patients with some
comorbidities [82–85].

The scientific data justifies the need for studies assessing the different
proinflammatory components of GCF in patients with HCV infection or with HCV
infection and periodontal disease. However, there are studies finding a high level of
some of these markers like interleukins IL-1, IL-6 and interferon IFN-gamma in the
serum of HCV-infected patients and also in the serum and GCF of patients with
periodontal infection [86–88]. Further studies are required to assess the link between
other inflammatory markers found in the gingival fluid and the HCV infection [20]
and thus to investigate if the HCV-infected patients would have a higher risk to
develop periodontal injury or if periodontal-compromised patients with type C
hepatitis could have a higher expression of other liver-specific biomarkers, along with
some insights into the underlying mechanism.

It was shown that the levels of AST in the GCF of patients with periodontal
disease are elevated and correlated with the periodontal disease activity [89, 90],
recording a declining trend after periodontal treatment and associating clinical
parameter improvement [91]. Moreover, in nonalcoholic fatty liver disease (NAFLD)
subjects, there is an important liver biomarker improvement (expressed as ALT and
AST activity) following efficient periodontal therapy. Thus, the periodontal
inflammation determined by P. gingivalis in NAFLD patients could be a risk factor
for the exacerbation of NAFLD, and the periodontal treatment could be useful in the
management of NAFLD subjects [92]. The mechanisms that have been considered to
be responsible for the implication of periodontitis in different liver diseases were
related to bacterial agents, proinflammatory mediators, and oxidative stress. Together
with cytokines and chemokines, other molecules such as heat shock proteins (HSPs)
could be produced as a result of periodontal bacterial aggression and could
consequently trigger hepatic inflammation [17]. Together with the pathological
mechanism proposed in Section 2.1 of this review article (IR involvement), the study
of TNF-alpha and other proinflammatory cytokines could provide a thorough
explanation for the possible chronic hepatitis C infection and periodontal disease
connection. Comprehensive understanding of the bidirectional pathological
mechanism that joins the two conditions is required in both periodontology and
hepatology fields in order to provide proper diagnostic and treatment protocols.

5. Conclusion

Through different means, HCV infection causes a decline in the oral health of
infected patients. Whether considered by some authors to be connected to
extrahepatic manifestations of the infection or derived from the systemic implications
(malfunction of the immune system) or caused by the patients’ behavior (poor oral
hygiene and diet), the periodontal impairment of HCV-infected patients accounts for
an important cutback of life quality and welfare. Moreover, viral RNA molecules and
antibodies have been identified in patients’ saliva and gingival fluid, raising further
questions about the disease’s transmission and detection.

The study of the common immunological link between type C viral hepatitis
and periodontal health can be the subject of further research, not only in what
concerns the clinical parameters but also through identification of specific markers in
GCF, exploring the merger of the pathological mechanisms, possibly related to IR and
chronic inflammatory process. This may lead to a better understanding upon whether
this relationship is bidirectional and implicitly upon the underlying mechanisms that
induce progression toward their pathologies. This bidirectional relationship between
periodontal disease and HCV infection has far-reaching implications for both patients
and medical practitioners, either periodontologists or hepatologists.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

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