Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2020

01-12-2020 | Fatty Liver | Study protocol

Efficacy and safety of PERIOdontal treatment versus usual care for Nonalcoholic liver disease: protocol of the PERION multicenter, two-arm, open-label, randomized trial

Authors: Yohei Kamata, Takaomi Kessoku, Tomoko Shimizu, Takashi Kobayashi, Takeo Kurihashi, Satsuki Sato, Syotaro Kuraji, Norio Aoyama, Tomoyuki Iwasaki, Shogo Takashiba, Nobushiro Hamada, Toshiro Kodama, Toshiyuki Tamura, Satoshi Ino, Takuma Higurashi, Masataka Taguri, Takeharu Yamanaka, Masato Yoneda, Haruki Usuda, Koichiro Wada, Atsushi Nakajima, Masato Minabe

Published in: Trials | Issue 1/2020

Login to get access

Abstract

Background

We report the first protocol for a multicenter, randomized comparison study to compare the efficacies of periodontal scaling and root-planing treatment against that of tooth-brushing treatment for nonalcoholic fatty liver disease (NAFLD) (PERION: PERIOdontal treatment for NAFLD). Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD, which can progress to cirrhosis and hepatocellular carcinoma. Increased endotoxemia is associated with the progression of NAFLD. Periodontal bacteria possess endotoxins; Porphyromonas gingivalis is well-known as a major pathogenic bacterium in periodontitis, and serum antibody levels for P. gingivalis are high in patients with periodontitis. Several reports have indicated that P. gingivalis is related to NAFLD. This study aims to investigate the effect of periodontal treatment for liver damage, P. gingivalis infection, and endotoxemia on patients with NAFLD.

Methods

We will include adult patients (20–85 years old) with NAFLD, alanine aminotransferase (ALT) ≥ 40 IU/L, and equivalent steatosis grade ≥ 1 (target sample size, n = 40 patients; planned number of patients with outcome data, n = 32). Participants will be randomly assigned to one of two groups: a scaling and root-planing group or tooth-brushing as the usual group. The primary outcome will be the change in ALT levels from baseline to 12 weeks; the key secondary outcome will be the change in the serum immunoglobulin G (IgG) antibody titer for P. gingivalis at 12 weeks.

Discussion

This study should determine whether periodontal treatment decreases liver damage, P. gingivalis infection, and endotoxemia in patients with NAFLD.

Trial registration

University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000022079.
Literature
1.
2.
Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005;22:1141–5.PubMedCrossRef
3.
Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin. 2010;26:2183–91.PubMedCrossRef
4.
Agopian VG, Kaldas FM, Hong JC, Whittaker M, Holt C, Rana A, et al. Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann Surg. 2012;256:624–33.PubMedCrossRef
5.
Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 2012;91:914–20.PubMedCrossRef
6.
Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Micorbiol. 2005;43:5721–32.CrossRef
7.
Bodet C, Chandad F, Grenier D. Pathogenic potential of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, the red bacterial complex associated with periodontitis. Pathol Biol (Paris). 2007;55:154–62.CrossRef
8.
Perez-Chaparro PJ, Gonçalves C, Figueiredo LC, Faveri M, Lobão E, Tamashiro N, et al. Newly identified pathogens associated with periodontitis: a systematic review. J Dent Res. 2014;93:846–58.PubMedPubMedCentralCrossRef
9.
Holt SC, Kesavalu L, Walker S, Genco CA. Virulence factors of Porphyromonas gingivalis. Periodontol 2000. 1999;20:168–238.PubMedCrossRef
10.
11.
Sun Y, Li H, Yang MF, Shu W, Sun MJ, Xu Y. Effects of aging on endotoxin tolerance induced by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli. PLoS One. 2012;7:e39224.PubMedPubMedCentralCrossRef
12.
Liang S, Krauss JL, Domon H, McIntosh ML, Hosur KB, Qu H, et al. The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss. J Immunol. 2011;186:869–77.PubMedCrossRef
13.
Kuraji R, Fujita M, Ito H, Hashimoto S, Numabe Y. Effects of experimental periodontitis on the metabolic system in rats with diet-induced obesity (DIO): an analysis of serum biochemical parameters. Odontology. 2018;106:162–70.PubMedCrossRef
14.
Nakahara T, Hyogo H, Ono A, Nagaoki Y, Kawaoka T, Miki D, et al. Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease. J Gastroenterol. 2018;53:269–80.PubMedCrossRef
15.
Yoneda M, Naka S, Nakano K, Wada K, Endo H, Mawatari H, et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterol. 2012;12:16.PubMedPubMedCentralCrossRef
16.
Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, Yasui K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:101–7.PubMedCrossRef
17.
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New Eng J Med. 2010;362:1675–85.PubMedCrossRef
18.
Suzuki A, Lymp J, St Sauver J, Angulo P, Lindor K. Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis. Liver Int. 2006;26:1209–16.PubMedCrossRef
19.
Kudo C, Naruishi K, Maeda H, Abiko Y, Hino T, Iwata M, et al. Assessment of the plasma/serum IgG test to screen for periodontitis. J Dent Res. 2012;91:1190–5.PubMedCrossRef
20.
American Academy of Periodontology. Comprehensive periodontal therapy: a statement by the American Academy of Periodontology*. J Periodontol. 2011;82:943–9.CrossRef
21.
Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–53.PubMedCrossRef
22.
Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology. 2015;61:1392–405.PubMedCrossRef
23.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65.PubMedCrossRef
24.
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–59.PubMedCrossRef
25.
Cadranel JF. Good clinical practice guidelines for fine needle aspiration biopsy of the liver: past, present and future. Gastroenterol Clin Biol. 2002;26:823–4.PubMed
26.
Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.PubMedCrossRef
27.
Sasso M, Beaugrand M, de Ledinghen V, Douvin C, Marcellin P, Poupon R, et al. Controlled attenuation parameter (CAP): a novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol. 2010;36:1825–35.PubMedCrossRef
28.
Obara N, Ueno Y, Fukushima K, Nakagome Y, Kakazu E, Kimura O, et al. Transient elastography for measurement of liver stiffness measurement can detect early significant hepatic fibrosis in Japanese patients with viral and nonviral liver diseases. J Gastroenterol. 2008;43:720–8.PubMedCrossRef
29.
Alisi A, Pinzani M, Nobili V. Diagnostic power of fibroscan in predicting liver fibrosis in nonalcoholic fatty liver disease. Hepatology. 2009;50:2048–9 author reply 2049-50.PubMedCrossRef
30.
Chang PE, Lui HF, Chau YP, Lim KH, Yap WM, Tan CK, et al. Prospective evaluation of transient elastography for the diagnosis of hepatic fibrosis in Asians: comparison with liver biopsy and aspartate transaminase platelet ratio index. Aliment Pharmacol Ther. 2008;28:51–61.PubMedCrossRef
31.
Chan WK, Nik Mustapha NR, Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2014;29:1470–6.PubMedCrossRef
32.
de Lédinghen V, Vergniol J, Capdepont M, Chermak F, Hiriart JB, Cassinotto C, et al. Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations. J Hepatol. 2014;60:1026–31.PubMedCrossRef
33.
Reeder SB, Robson PM, Yu H, Shimakawa A, Hines CD, McKenzie CA, et al. Quantification of hepatic steatosis with MRI: the effects of accurate fat spectral modeling. J Magn Reson Imaging. 2009;29:1332–9.PubMedPubMedCentralCrossRef
34.
Permutt Z, Le TA, Peterson MR, Seki E, Brenner DA, Sirlin C, et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease – MRI accurately quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther. 2012;36:22–9.PubMedPubMedCentralCrossRef
35.
Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150:626–37.PubMedCrossRef
36.
Yoneda M, Yoneda M, Fujita K, Inamori M, Tamano M, Hiriishi H, et al. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut. 2007;56:1330–1.PubMedPubMedCentralCrossRef
37.
Furuta M, Ekuni D, Yamamoto T, Irie K, Koyama R, Sanbe T, et al. Relationship between periodontitis and hepatic abnormalities in young adults. Acta Odontol Scand. 2010;68:27–33.PubMedCrossRef
38.
Saito T, Shimazaki Y, Koga T, Tsuzuki M, Ohshima A. Relationship between periodontitis and hepatic condition in Japanese women. J Int Acad Periodontol. 2006;8:89–95.PubMed
39.
Ahmad A, Furuta M, Shinagawa T, Takeuchi K, Takeshita T, Shimazaki Y, et al. Association of periodontal status with liver abnormalities and metabolic syndrome. J Oral Sci. 2015;57:335–43.PubMedCrossRef
40.
Morita T, Yamazaki Y, Fujiharu C, Ishii T, Seto M, Nishinoue N, et al. Serum γ-glutamyltransferase level is associated with periodontal disease independent of drinking habits in Japanese adults. Med Sci Monit. 2014;20:2109–16.PubMedPubMedCentralCrossRef
41.
Furusho H, Miyauchi M, Hyogo H, Inubushi T, Ao M, Ouhara K, et al. Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice. J Gastroenterol. 2013;48:1259–70.PubMedCrossRef
42.
Arimatsu K, Yamada H, Miyazawa H, Minagawa T, Nakajima M, Ryder MI, et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci Rep. 2014;4:4828.PubMedPubMedCentralCrossRef
43.
Nakajima M, Arimatsu K, Kato T, Matsuda Y, Minagawa T, Takahashi N, et al. Oral administration of P gingivalis induces dysbiosis of gut microbiota and impaired barrier function leading to dissemination of enterobacteria to the liver. PloS One. 2015;10:e0134234.PubMedPubMedCentralCrossRef
44.
Matsuda Y, Kato T, Takahashi N, Nakajima M, Arimatsu K, Minagawa T, et al. Ligature-induced periodontitis in mice induces elevated levels of circulating interleukin-6 but shows only weak effects on adipose and liver tissues. J Periodontal Res. 2016;51:639–46.PubMedCrossRef
45.
The Helsinki Declaration of the World Medical Association (WMA). Ethical principles of medical research involving human subjects. Pol Merkur Lekarski. 2014;36:298–301.
46.
Miyazawa Y. Diagnostic tests approved by Ministry of Health and Welfare (September/October 2011). Rinsho Byori. 2011;59:1055–62.PubMed
47.
Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Ann Inter Med. 2010;152:726–32.CrossRef
Metadata
Title
Efficacy and safety of PERIOdontal treatment versus usual care for Nonalcoholic liver disease: protocol of the PERION multicenter, two-arm, open-label, randomized trial
Authors
Yohei Kamata
Takaomi Kessoku
Tomoko Shimizu
Takashi Kobayashi
Takeo Kurihashi
Satsuki Sato
Syotaro Kuraji
Norio Aoyama
Tomoyuki Iwasaki
Shogo Takashiba
Nobushiro Hamada
Toshiro Kodama
Toshiyuki Tamura
Satoshi Ino
Takuma Higurashi
Masataka Taguri
Takeharu Yamanaka
Masato Yoneda
Haruki Usuda
Koichiro Wada
Atsushi Nakajima
Masato Minabe
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-020-4201-y

Other articles of this Issue 1/2020

Trials 1/2020 Go to the issue

Study protocol

Antioxidant dressing therapy versus standard wound care in chronic wounds (the REOX study): study protocol for a randomized controlled trial

Study protocol

Glioma patients in outpatient care—optimization of psychosocial care in neuro-oncological patients (GLIOPT): Protocol for a cluster randomized controlled trial

Methodology

A simulation study comparing the power of nine tests of the treatment effect in randomized controlled trials with a time-to-event outcome

Study protocol

Opposing needling for analgesia and rehabilitation after unilateral total knee arthroplasty: a randomized, sham-controlled trial protocol

Letter

Efficacy and safety of Anluohuaxian in the treatment of patients with severe Coronavirus disease 2019- a multicenter, open label, randomized controlled study: a structured summary of a study protocol for a randomised controlled trial

Update

OPTimal IMAging strategy in patients suspected of non-traumatic pulmonary disease at the emergency department: chest X-ray or ultra-low-dose chest CT (OPTIMACT) trial—statistical analysis plan