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

Kamata et al. Trials (2020) 21:291 https://doi.org/10.1186/s13063-020-4201-y STUDY PROTOCOL Open Access Efficacy and safety of PERIOdontal treatment versus usual care for Nonalcoholic liver disease: protocol of the PERION multicenter, two-arm, open-label, randomized trial Yohei Kamata1†, Takaomi Kessoku2†, Tomoko Shimizu1†, Takashi Kobayashi2, Takeo Kurihashi3, Satsuki Sato1, Syotaro Kuraji1, Norio Aoyama4, Tomoyuki Iwasaki5, Shogo Takashiba6, Nobushiro Hamada7, Toshiro Kodama8, Toshiyuki Tamura1, Satoshi Ino9, Takuma Higurashi2, Masataka Taguri10, Takeharu Yamanaka10, Masato Yoneda2, Haruki Usuda11, Koichiro Wada11, Atsushi Nakajima2 and Masato Minabe4* 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. (Continued on next page) * Correspondence: † Yohei Kamata, Takaomi Kessoku and Tomoko Shimizu contributed equally to this work. 4 Division of Periodontology, Department of Oral Interdisciplinary Medicine, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa 238-8580, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kamata et al. Trials (2020) 21:291 Page 2 of 11 (Continued from previous page) 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. Keywords: NAFLD, Porphyromonas gingivalis, Periodontal treatment, Lipopolysaccharides, Alanine aminotransferase, Immunoglobulin G Background The broad spectrum of fatty liver diseases in individuals who consume little-to-no alcohol is called nonalcoholic fatty liver disease (NAFLD) and includes nonalcoholic steatohepatitis (NASH). NASH is an increasingly common cause of chronic liver disease worldwide and is associated with increased liver-related mortality and hepatocellular carcinoma [1–3]. NASH progresses to cirrhosis in 15–20% of the affected individuals and is a rising indication for liver transplantation [4]. However, approved therapies for NASH have not yet been established; therefore, preventive therapies to inhibit the progression of fatty liver disease to NASH are required. Periodontal disease is an infectious disease of the gums and tissues surrounding the teeth and causes tooth loss resulting from the destruction of tooth-supporting tissues. The incidence rate of periodontitis is > 47% in adults in the USA [5]. More than 700 bacterial species or phylotypes have been detected in the oral cavity [6]. Some species/ complexes are closely associated with advanced periodontal lesions, such as Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans [7, 8]. Among them, P. gingivalis, a gram-negative anerobic bacterium, is the major etiologic agent that contributes to periodontal disease progression and bone and tissue destruction [9, 10]. The lipopolysaccharide (LPS) cell-wall component of P. gingivalis is one of the virulence factors that trigger a wide range of host responses, including the production of proinflammatory cytokines, anti-inflammatory cytokines, and chemokines [11]. These cytokines and inflammatory mediators play important roles in the progression of periodontitis at the stage where host immune and inflammatory responses lead to the destruction of periodontal tissue under the influence of multiple behavioral, environmental, and genetic factors [12]. Recently, several studies have reported the relationship between NAFLD and periodontal disease [13, 14]. Yoneda et al. [15] reported that the detection frequency of P. gingivalis in the saliva of patients with NAFLD and patients with NASH was significantly higher than that in nonNAFLD control subjects. Moreover, they presented preliminary evidence to suggest that nonsurgical periodontal treatments in 10 patients with NAFLD for 3 months ameliorated the liver function parameters, such as the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Consequently, it is thought that infection with a periodontal pathogen, mainly P. gingivalis, is associated with fibrosis severity in patients with NAFLD and that the prevention and elimination of P. gingivalis infection by periodontal treatment may have a beneficial effect on the management of NA (...truncated)