口 腔 病 理 科 Systemic diseases and oral cavity 全身性疾病與口腔之關係 陳玉昆副教授: 高雄醫學大學 口腔病理科 07-3121101~2755 yukkwa@kmu.edu.tw

學 習 目 標 Relationships between chronic oral infectious diseases & systemic diseases 2. Systemic diseases manifested in oral cavity

參考資料 References 1. 董醒任 口腔疾病與全身健康的關係 Happy Teeth 2000年9月15日 p.5-10 2. Okuda K & Ebihara Y. Relationships between chronic oral infectious diseases & systemic diseases. Bull Tokyo Dent Coll 1998;39:165-74 3. Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1999;70:793-802 4. Sakane T et al. Behcet’s disease. New Eng Med J 1999;341:1284-91 5. Kaohsiung Medical University, Oral Pathology Department 6. O’Brien SJ & Dean M. In search of AIDS-resistance genes. Sci Am 1997;177:44-53 7. Mann JM & Tarantola DJM. Improving HIV therapy. Sci Am 1998;279:64-67 8. Regezi JA et al. Oral Kaposi’s sarcoma: Biopsy accessions as an indication of declining incidence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:399 9. Sharquie KE. et al. Oral pathergy test in Behcet's disease. Br J Dermatol 2002;168-9 10. Crispian Scully Handbook of oral disease diagnosis & management Chapter 4, p.148-9 11. Cawson RA et al. Oral Disease 3rd edition, p.14.14 12. Jin LJ et al. Are periodontal diseases risk factors for certain systemic disorders- what matters to medical practitioners? Hong Kong Med J 2003;9:31-7 13. Chen YK et al. Intra-oral HIV-associated Burkitt’s lymphoma with mandible involvement: a case report. Oral Oncol 2005; 41: 249-52 14. Zhang Y et al. The emerging landscape of salivary diagnostics. OHDM 2014;13:200-10 15. Woo VL. Oral manifestations of Crohn’s disease: A case report & review of the literature. Case Rep in Dent 2015, Article ID 830472.

Systemic Diseases & Oral Cavity Subtopics Relationships between chronic oral infectious diseases & systemic diseases Systemic diseases manifested in oral cavity Oral cavity Systemic diseases bacteria

Systemic Diseases & Oral Cavity 1. Oral bacteria causing bacterial endocarditis Bacterial endocarditis bacteremia Blood smear of sepsis Ref: 2

Systemic Diseases & Oral Cavity 2. Relationships of periodontobacteria and cardiovascular diseases 牙 周 感 染 與 心 臟 血 管 疾 病 的 關 係 Ref: 1

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (epidemiological view) LCL: lower confidence limit UCL: upper confidence limit OHI: Oral Hygiene Index Percentile OHI value Estimate of odd ratio LCL UCL Ref: 3

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (pathway) Silent aspiration Colonization Ref: 2

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (cytokine) Trachea Bronchus (細胞素) IL: interleukin TNF: tissue necrosis factor Cytokine Ref: 3

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (four mechanisms) Mechanism (1) (Respiratory pathogen) H. influenzae (Enzyme) Protease P. gingivalis (Dental pathogen) 1. Mucosal surface receptor alteration by protease 2. Aspiration into lung Ref: 3

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (four mechanisms) Mechanism (2) 2. Salivary pellicle P. gingivalis degradation by protease H. influenzae 1. Salivary pellicle prevents respiratory pathogen adhere to mucosal surface 3. Respiratory pathogen adhere to mucosal surface Ref: 3

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (four mechanisms) Mechanism (3) H. influenzae P. gingivalis 1. Salivary pellicle Mucous layer degradation by protease 2. Exposure of adhesion receptor for respiratory pathogen Salivary pellicle Ref: 3

Systemic Diseases & Oral Cavity 3. Pathogens for bacterial pneumonia in oral cavity (four mechanisms) Mechanism (4) H. influenzae Salivary cytokines (IL, TNF) 1. Upregulation of adhesion receptor on mucosal surface by cytokines 2. Promotion of respiratory pathogens colonization Ref: 3

Systemic Diseases & Oral Cavity Biomolecules & fluids from different sources constitute the saliva Source 2 Oral mucosa cells Source 1 Salivary gland Source 3 Oral microbiota & viruses Source 4 Blood Source 5 Gingival crevicular fluid Source 6 Food SALIVA A complete mixture of DNAs, RNAs & proteins originated from several sources Ref: 14

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases Nephritis Arthritis Refs: 2, 5

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases Metastatic infection from oral cavity Endocarditis Brain abscess Sinusitis Ludwig’s angina Orbital cellulitis Osteomyelitis Skin ulcer Pustulosis palmaris et plantaris

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases Metabolic injury by oral bacterial toxin Coronary heart disease Abnormal pregnancy outcome Persistent pyrexia Idiopathic trigeminal neuralgia Atypical facial pain Acute myocardial infarction

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases Metastatic inflamma- tion by oral bacteria Bechet’s disease Crohn’s disease Inflammatory bowel disease Uveitis

Systemic Diseases & Oral Cavity Criteria for diagnosis 4. Oral chronic infectious diseases cause secondary diseases - Bechet’s disease Criteria for diagnosis Findings Definitions Recurrent oral ulceration Eye lesions Skin lesions Positive pathergy test Recurrent genital Minor aphthous, major aphthous, or hepetiform ulcers observed by the physicians or patients, which have occurred at least three times over a 12 month period Aphthous ulceration or scarring observed by the physician or patient Erythema nodosum observed by the physician or patient, pseudofolliculitis, or papulopustular lesions or acneriform observed by the physician in a postadolescent patient who is not receiving corticosterioids Anterior uveitis, posterior uveitis or cells in the vitreous on slite lamp examination or retinal vasculitis detected by an ophthalmologist Test interpreted as positive by the physician at 24 to 48 hours Criteria: recurrent oral ulceration + ≥ 2 others findings Ref: 4

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases - Bechet’s disease Pricking a sterile needle into the patient’s forearm or lower lip. The results are judged to be positive when the puncture causes an aseptic erythematous nodule/pustule that is > 2mm in diameter at 24 to 48 hours. At the reaction site there is initially an accumulation of neutrophils, followed by the accumulation of mononuclear cells Skin test Oral test Forearm Lower lip Ref: 9

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases - Bechet’s disease Erythema/Papule/Pustule--Diameter Definition of different grades of skin pathergy test Grade of test Clinical characteristic of the test at 48 h Negative (-) Suspect (+/-) Positive (+) Only erythema <2 mm Only erythema > 3 mm or papule 1-2 mm + erythema < 2 mm 1+ Papule 2-3 mm + erythema > 3 mm 2+ Papule > 3 mm + erythema > 3 mm 3+ Pustule 1-2 mm + erythema > 3 mm 4+ Pustule > 2 mm + erythema > 3 mm Ref: 9

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases - Bechet’s disease Oral ulcer Genital ulcer A horizontal layer of inflammatory cells Hypopyon Erythema nodosum Ref: 4

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases – Crohn’s disease Oral manifestations of Crohn’s disease Lesion Site(s) Characteristics Persistent mucosal swelling Lips, buccal mucosa Labial enlargement, firm to palpation, typically painless Cobblestoning of mucosa Buccal mucosa, vestibule Mucosal edema with or without fissuring Mucogingivitis Attached gingiva, alveolar mucosa Patchy erythematous macules or plaques with or without hyperplasia Linear ulcerations Vestibule, buccal mucosa, tongue, palate Deep ulcerations with or without hyperplastic margins Mucosal tags or polyps Hyperplasia of mucosa, firm or boggy to palpation Ref: 15

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases – Crohn’s disease Labial swelling & fissuring Ulceration Cobblesing stone mucosa Mucosal tag Ref: 4

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases – Crohn’s disease Mild mucosal erythema of the right anterior maxillary gingiva Ref: 15

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases – Crohn’s disease 2 1 3 Ref: 15 1. Nodular swellings of the interdental papillae between the right permanent mandibular central and lateral incisors and primary canine 2. An ulceration of the free gingival margin between the incisors is seen 3. Linear ulceration with hyperplasticmargins involving the alveolar mucosa

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases – Crohn’s disease A demarcated area of mucosal erythema involving the left anterior maxillary alveolar mucosa Ref: 15

Systemic Diseases & Oral Cavity 4. Oral chronic infectious diseases cause secondary diseases – Crohn’s disease Low-power view showing stratified squamous epithelium with scattered intraepithelial lymphocytes. The underlying fibrous connective tissues are characterized by a patchy chronic inflammatory cell infiltrate & an isolated granuloma (arrow) High-power view showing a well-defined, noncaseating granuloma composed predominantly of epithelioid histiocytes & lymphocytes Ref: 15

Systemic Diseases & Oral Cavity 5. Heat shock proteins producing by oral bacteria may induce dermal diseases Dermatitis Ref: 2

Systemic Diseases & Oral Cavity 6. Gingivitis pathogens cause pregnancy disorders Prevotella intermedia Porphyromonas gingivalis Toxin: lipopolysaccharide Estrogen Ref: 2

Systemic Diseases & Oral Cavity 6. Gingivitis pathogens cause pregnancy disorders Ref: 1

Systemic Diseases & Oral Cavity 7. Periodontitis and diabetic mellitus 牙周 病 糖 尿 病 Ref: 1

Systemic Diseases & Oral Cavity Periodontal infection & systemic conditions - potential linkage & possible pathogenic mechanisms Periodontal infection Cardiovascular diseases Diabetes mellitus Adverse pregnancy outcomes Pulmonary infections Ref: 12

Systemic diseases manifested in oral cavity Ref: 5

Virus (病毒) Life cycle Attachment Penetration translocate endocytosis fusion Uncoating Replication Release Attachment HIV gp 120 gp 41 CCR5 Ref: 6

Attachment Gp120能與CD4受體結合， 但無法直接引導HIV進入 host cell CCR5將gp120拉開後， gp41引導HIV進入 host cell Host cell Ref: 5

Life - Cycle Possible ways of HIV therapy Attachment gp 41 Attachment Life - Cycle Reverse transcriptase Integrase Protease Possible ways of HIV therapy Drugs block binding (attachment & fusion) Drugs inhibit reverse transcriptase Drugs under study would inhibit integrase Some existing drugs inhibit protease Other Host cell Infected other host cells CCR5 Attachment gp 120 脂質套膜 套膜蛋白 Integration CD4 Budding Host cell Integrase Nucleus HIV RNA Nucleus Fusion HIV mRNA Reverse- transcription Protease 蛋白質外殼 H I V gp 41 Reverse- transcriptase Cytoplasm Caspid Cytoplasm Uncoating Ref: 5

受體 CD4 CCR5 Macrophage T-cell Early stage Late stage Ref: 5

Virus (病毒) Acute phase AIDS Chronic phase CD4 T-cell count Viral load Ref: 7

Oral Manifestations of AIDS Candidiasis (thrush) Candidiasis (atrophic) Kaposi sarcoma Necrotizing gingivitis Ref: 10

Oral Manifestations of AIDS Hairy leukoplakia H&E EBV Ref: 11

Oral Manifestations of AIDS Oral Kaposi’s sarcoma: Biopsy accessions as an indication of declining incidence 至2013年底，國內愛滋感染者的服藥人數為1萬4983人，其中有8成體內測不到病毒量，目前在雞尾酒療法及規律服藥下，感染愛滋病毒已被視為一種慢性病，台灣最年長的愛滋感染者>90歲 203 Oral KS cases/year N = 203 Due to highly active antiretroviral therapy in 1995 No. of cases 2002 1981 1991 1997 Twenty-year incidence of KS at the University of California San Francisco Ref: 8

Oral Manifestations of AIDS Hairy leukoplakia Our Collected Case 疾管署統計2013年國內新增愛滋感染者2244人，757人已發病(34%)；已發病者約53%在6個月內發病 Oral candidiasis Ref: 5

Oral Manifestations of AIDS Our Collected Case – Burkitt’s lymphoma Refs: 5, 13

Oral Manifestations of AIDS Our Collected Case – Burkitt’s lymphoma CD-20 c-myc Ki-67 p53 Oral Oncol Extra 2005:41:249-52. Refs: 5, 13

Oral Manifestations of TB Ref: 5

Oral Manifestations of TB Figure 1 47 Ref: 5

Oral Manifestations of TB C Figure 1 48 Ref: 5

Relationships between chronic oral infectious diseases & systemic Summaries Knowing: Relationships between chronic oral infectious diseases & systemic diseases 2. Systemic diseases manifested in oral cavity - AIDS, TB

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