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肝炎防治三總基隆分院胃腸肝膽科曾美瑜醫師

國人肝病現況每年約 13000 人死於慢性肝病肝硬化 (4975 人 ) 及肝癌 (8116 人 ) 台灣肝癌病因

經驗分享名人罹患肝病已過世國父孫中山烹飪專家傅培梅美爵士歌手雷鬼副總統陳誠喜劇泰斗許不了搖滾歌手薛岳 ICRT 的 DJ 大衛王畫家楊三郎抗病中立委高金素梅立委蘇起施明德演員石英永豐餘紙業何壽川南部鋼鐵大王林義守您會用那些方式改善預防肝功能不佳? 改善預防不熬夜多休息 58.8 73.5 定期檢查看醫生吃藥控制 45 7.0 多吃蔬菜不喝酒抽菸做好飲食控制 41.3 55.1 吃偏方 ( 自製藥膳 ) 20.4 10.5 吃市面上健康養生食品 12.4 11.2 多運動 8.1 9.8 多穿衣服注意保暖 / 注意飲食習慣與衛生 0.5 2.8 定期檢查看醫生吃藥 7.0 都沒有 6.5 5.8 康健雜誌 4

小心肝肝病的危險因子 5 家族病史 ( 肝炎帶原者慢性肝炎脂肪肝肝硬化肝癌 ) 壓力過大熬夜抽菸酗酒攝取黃麴毒素污染的食物 ( 花生玉米米等儲存不當的五穀類 )

肝臟的生理功能代謝作用轉化作用解毒與排泄功能 ( 酒精藥物膽紅素尿素等廢物 ) 蛋白質合成排泄功能

有苦說不出肝病症狀肝火旺?= 肝功能不好前兆噁心嘔吐食慾不振疲倦黃疸茶色尿腹水

Causes of Hepatitis Infective Hepatotropic virus: HAV, HBV, HCV, HDV, HEV HSV, CMV, EBV, VZV, SARS Marburg virus, Lassa virus, Ebola virus Drugs reaction and toxins Acetaminiphen overdose Halothane Isoniazid-rifampicin NSAID Mushroom poisoning Herbal remedies Alcoholic hepatitis Ischemic Ischemic hepatitis Surgical shock Metabolic Wilson s disease Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) Reye s disease Hemochromatosis Autoimmune Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis

Source of virus feces blood/ blood-derived body fluids Route of transmission fecal-oral percutaneous permucosal Viral Hepatitis Type of Hepatitis A B C D E blood/ blood-derived body fluids percutaneous permucosal blood/ blood-derived body fluids percutaneous permucosal feces fecal-oral Chronic infection no yes yes yes yes Prevention pre/postexposure immunization pre/postexposure immunization blood donor screening; risk behavior modification pre/postexposure immunization; risk behavior modification ensure safe drinking water

Hepatitis A Virus Nucleic acid: ssrna, ~7500 nucleotides Classification: picornavirus Serotype: one Fecal-oral route <2y/o: <20% symptomatic, >5y/o: >80% symptomatic Complete recovery: 60% in 2 months, all by 6Ms

NATURAL HISTORY OF ACUTE HEPATITIS A Martin and Lemon. Hepatology 2006;43: S164-172

診斷 anti-hav IgG anti-hav IgG + 曾感染過 A 型肝炎或是曾接受 A 肝疫苗注射. 目前已有免疫力 _ 未感染過 A 型肝炎病毒而且對 A 型肝炎病毒沒有免疫力, 仍有可能被感染, 建議接受 A 型肝炎疫苗注射, 增加免疫力 anti-hav IgM + 目前正感染急性 A 型肝炎 12

流行病學 A 型肝炎主要流行地區包括亞洲, 非洲與南美洲等地區, 尤以東南亞大陸等地區在臺灣 ( 尤指都會地區 ), 大部份兒童及青少年都未具有 A 型肝炎抗體 ( 易感族群 ) ƒ A 型肝炎可能在未具保護力之族群間爆發流行縣市別病例數台北市 125 台中市 61 台南市 6 高雄市 16 基隆市 8 新竹市 11 嘉義市 0 新北市 152 桃園市 43 CDC

防治工作注意飲水及飲食衛生保持良好衛生習慣注意環境衛生, 特別是廁所環境清潔針對高危險群 : (1) 慢性肝炎患者 (2) 醫護工作者 (3) 凝血功能異常者 (4) 小孩及在托嬰中心照顧小孩的工作者 (5) 處理食物的工作者 (6) 前往 A 型肝炎高流行地區旅遊或工作者, 或 30 歲以下未具 A 型肝炎抗體者, 加強宣導自費疫苗接種餐飲醫療照護及幼兒保育工作者, 於發病後應停業至少一週, 避免造成疫情擴大旅遊前的諮詢及預防 : (1) 前往 A 型肝炎高感染地區工作或旅遊者, 加強個人飲食飲水衛生宣導 (2) 至流行國家, 未具 A 型肝炎抗體者, 衛教出國前 1 個月接種 A 型肝炎疫苗,6-12 個月後再接種一劑第一劑接種後可獲得約 80-98% 左右的保護力, 完成二劑接種後, 可提供 20 年的保護力

The HBV Genome pres1 pres2 Relaxed circular partially double-stranded DNA Approximately 3,219 bps Four overlapping open reading frames (-) (+) S Core DR1 DR2 POL Pre-core Adapted from Lee WM. N. Engl. J. Med. 1997; 337:1733 45 X

S P C CORE PROMOTER A1762T G1764A e X STOP-CODON AT CODON 28 OF PRE-CORE REGION G1896A

Ghany M, Liang TJ. Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. Gastroenterology 2007; 132: 1574-85

流行病學 High Intermediate Low Carrier rate, percent 8 percent(60-80%life time) 2-7 percent(20-60%) 1 percent Geographic distribution Predominant age at infection Predominant mode of infection Southeast Asia; China; Pacific islands; sub- Saharan Africa; Alaska (Eskimos) Mediterranean basin; eastern Europe; central Asia; Japan; Latin and South America; Middle East Perinatal and early childhood Early childhood Adult United States and Canada, western Europe; Australia; New Zealand Maternal-infant; percutaneous Percutaneous; sexual Sexual(40%); percutaneous

Liaw & Chu. Lancet 2009 Three Phases + One Variant Phase of CHB Immune tolerant phase Immune clearance phase Inactive residual phase Reactivation IU/ml 2x10 9 2x10 4 HBV DNA HBeAg-positive Anti-HBe-positive HBeAg reversion HBeAgnegative hepatitis Pre C/BCP Wild type Wild > Mutant Mutant > Wild Mutant HCC Cirrhosis HCC HBsAg loss Cirrhosis ALT Histology Minimal Active hepatitis Minimal/inactive Active hepatitis Liver HBcAg Nucleus Nucleus/cytoplasm Absent Nucleus/cytoplasm Age 20 35 60 35 year

Schematic representation of factors that influence the progression of HBV-related liver disease Host Factors Age> 40 years Gender: Male> Female Immune status Environmental factors Alcohol Smoking Aflatoxin exposure Concurrent HCV, HDV, HIV infection Viral Factors Genotype: C> B;D>A Viral load:> 10 4 copies/ml Genome Mutations: pre-s deletion, T1762/A1764 Liaw YF, Factors influencing liver disease progression in chronic hepatitis B. Liver International 2006; 26: 23-29

診斷 24 HBsAg Anti-HBs Anti-HBc 臨牀意義 + - - - + + - + - - - - - - + B 肝帶原者曾經感染過 B 肝, 但已對 B 肝有免疫力因為施打疫苗, 而對 B 肝有免疫力未曾接觸 B 肝, 趕快去打疫苗或已施打疫苗而無法產生免疫力曾感染 B 肝, 而無法產生抗體

Hepatitis B Diagnostic Tools * Markers of the virus HBV DNA HBeAg HBsAg * Markers of liver damage ALT AST Bilirubin *Antibodies to the virus Anti-HBc Anti-HBe Anti-HBs * Severity of liver damage (reserve) Bilirubin Albumin Prothrombin time Liver biopsy

台灣 B 型肝炎與肝癌相關之危險性 HBsAg HBeAg ALT Risk - - Normal 1 (23/71,105 person/yr) - - Elevated 5.4 + - Normal 10.3 + - Elevated 29.3 + + Normal 61.3 + + Elevated 109 Yang et al NEJM, 2002; 347:168-74

HBV Treatment: 2014 1957 Interferon discovered 1990 PMEA anti-hbv activity discovered 1991 3TC anti-hbv and anti-hiv activity discovered 1998 Entecavir anti-hbv activity discovered 2001 Telbivudine anti-hbv activity discovered 1991 Interferon alfa-2b approved for HBV 1998 Lamivudine (3TC) approved as first nucleoside analogue for HBV 2002-9 Adefovir dipivoxil (PMEA prodrug) approved for HBV 2006-10 Telbivudine approved for HBV 2005-4 Entecavir / 2005-5 peginterferon alfa-2a approved for HBV 2008-8 Tenofovir approved for HBV

Preferred initial treatment strategies according to various patient features Interferon Nucleoside analogs Age < 60, otherwise healthy Baseline HBV DNA 10 9 copies/ml Any age adult, nonserious comorbid illness Baseline HBV DNA > 10 10 copies/ml Baseline ALT > 2-3 x ULN Baseline ALT > 5 x ULN Genotype A or B Any genotype No cirrhosis Cirrhosis, with or without decompensation HBsAg-positive chemotherapy Perrillo RP. Therapy of hepatitis B-viral suppression or eradication? Hepatology 2006; 43: S182-S193

Drug resistance-na Lamivudine resistance: add tenofovir (add adefovir if tenofovir not yet available) (B1). Adefovir resistance: - N236T substitution: add lamivudine, entecavir or telbivudine or switch to tenofovir plus emtricitabine; - A181T/V substitution: add entecavir or switch to tenofovir plus emtricitabine) (B1). Telbivudine resistance: add tenofovir (add adefovir if tenofovir not yet available) (C1). Entecavir resistance: Add tenofovir (C1). Tenofovir resistance: resistance to tenofovir has not been described so far (B1). EASL 2009

Strategy for preventing CHB-HCC

防治工作 1. 衛生教育 -(1) 避免不必要的輸血打針針灸刺青穿耳洞等行為 (2) 養成良好個人衛生習慣, 不與別人共用 (3)B 型肝炎帶原者需特別注意防範傳染他人, 尤其是工作上常需接觸傷口之醫療人員及牙醫 (4) 避免多重性伴侶及嫖妓, 並採取安全性行為 2. 預防接種 -(1) 孕婦懷孕 7 8 個月時應接受 B 型肝炎產前篩檢 (2) 所有嬰幼兒於出生後 24 小時內 ( 儘速接種 ) 1 個月 6 個月, 應完成三劑 B 型肝炎疫苗接種 (3) B 型肝炎感染高危險群 ( 血液透析病人器官移植病人接受血液製劑治療者免疫不全者多重性伴侶注射藥癮者同住者或性伴侶為帶原者等 ) 如未曾感染 B 型肝炎病毒且經檢驗為 B 型肝炎病毒表面抗體陰性, 建議接種 3 劑 B 型肝炎疫苗, 以降低感染風險 ; 但曾於嬰幼兒時期接種 B 型肝炎疫苗者, 可採追加 1 劑 B 型肝炎疫苗,1 個月後再抽血檢驗, 如表面抗體仍為陰性 (< 10 miu/ml), 可依 0-1-6 個月之時程接續完成, 如經此補種仍無法產生抗體者, 則無需再接種, 惟仍應採取 B 型肝炎之相關預防措施, 並定期追蹤 B 型肝炎表面抗原 (HBsAg) 之變化

HCV Characteristics Family Flaviviridae Positive-sense single-stranded RNA (9.6 kb) 3000-amino acid polyprotein No RNA polymerase proofreading ability Quasispecies T ½ : 2.7 hours Daily production: 10 trillion (10 12 ) virions

HCV life cycle

HCV Characteristics

HCV Infection: extrahepatic Manifestations Haematological Mixed cryoglobulinemia Aplastic anaemia Thrombocytopenia Non-Hodgkin s b-cell lymphoma Dermatological Porphyria cutanea tarda Lichen planus Cutaneous necrotising vasculitis Renal Glomerulonephritis Nephrotic syndrome Endocrine Anti-thyroid antibodies Diabetes mellitus Salivary Sialadenitis Ocular Corneal ulcer Uveitis Vascular Necrotising vasculitis Polyarteritis nodosa Pulmonary fibrosis Neuromuscular Weakness/myalgia Peripheral neuropathy Arthritis/arthralgia Autoimmune Phenomena CREST syndrome Granuloma Autoantibodies Hadziyannis. J Eur Acad Dermatol Venereol. 1998.

Transmission unknown: 9-27% 65 % BT: 1in 2 million units

Clinical manifastation

The Natural History of HCV Infection ~ Variability from Person to Person LAUER GM.NEJM 2001

Natural History of HCV Infection Resolved Exposure (Acute phase) 15% (15) 85% (85) Stable Chronic 80% (68) Slowly Progressive 20% (17) Cirrhosis 75% (13) HIV and Alcohol 25% (4) HCC Transplant Death Alter MJ Semin Liver Dis 1995; 15: Management of Hepatitis C NIH Consensus Statement 1997; March 24-26:15(3).

AASLD 2009 HCV Guidelines: PegIFN/RBV Regimens Genotype 1/4 PegIFN alfa-2a PegIFN alfa-2b PegIFN dose (weekly) 180 µg 1.5 µg/kg RBV dose (daily) 1000 mg if 75 kg 1200 mg if > 75 kg 800 mg if 65 kg 1000 mg if > 65 to 85 kg 1200 mg if > 85 to 105 kg 1400 mg if >105 kg Planned duration 48 wks 48 wks Genotype 2/3 PegIFN alfa-2a PegIFN alfa-2b PegIFN dose (weekly) 180 µg 1.5 µg/kg RBV dose (daily) 800 mg 800 mg Planned duration 24 wks 24 wks Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Side Effects of IFN and RBV Treatment Flu-like symptoms: headache, fatigue, asthenia, myalgia, arthralgia, fever, chills Nausea, anorexia, aiarrhea Psychiatric symptoms: depression, insomnia Alopecia Haemolytic anaemia Teratogenicity Cough and dyspnoea Rash and pruritus Insomnia Anorexia Injection-site reaction Leukopenia, thrombocytopenia Thyroiditis Autoimmunity

Treatment Algorithm RVR EVR

Milestones of therapy for Chronic hepatitis C

C 肝全口服 DAA 新藥及作用機轉

Hepatitis Delta Virus (HDV) Defective RNA virus, 1.7 kb, circular single-stranded (minus strand), viroids (plant satellite viruses) Envelope: surface antigen of HBV L-HDAg: 214 a.a; S-HDAg: 195 a.a Co-infection and Super-infection 8 genotypes Type I: Predominant type in the word. Type II: Taiwan, Japan. Type III: South America Type IV: Recombination of genotypes I & II. Type V-VIII: Africa Genotype II HDV is less associated with fulminant hepatitis or unfavorable long-term outcome than is Genotype I (Wu JC, et al. Lancet 1995;346:939)

Chronic Delta Hepatitis Superinfection: >80% chronic hepatitis D Hepatitis D virus infection is decreasing in Taiwan and Italy. Treatment: Interferon: high dose, relapse after withdrawal; but long-term benefit (clinical outcome and survival) of interferon alpha therapy of CHD. (Gastroenterology 2004;126:1740-9) Lamivudine: ineffective

Peg-INF for tx CHD Wedemeyer H, et al. NEJM 2011 ; 364 : 322-31

Hepatitis E - Clinical Features Incubation period: Average 40 days Range 15-60 days Case-fatality rate: Overall, 1%-3% Pregnant women, 15%-25% Illness severity: Increased with age Chronic sequelae: In patient with HIV infection, patient with hematological malignancy receiving chemotherapy; and those receiving solid-organ transplantation Kamar N, et al. NEJM 2014 ;370 :1111-20

Transmission

Treatment Supportive Anti HEV IgG: non protective. Immunoglobulin: no effect pre- or postexposure Vaccine(?): 56% only have protective level 2 years later

E 型肝炎若孕婦感染, 其死亡率比一般人高出許多目前檢測 E 型肝炎的試劑未普及預防方面 : 要注意飲食衛生治療方面 : 支持性療法

響應 728 世界肝炎日 - 全民保肝護肝, 不做肝苦人 WHO2015 世界肝炎高峰會 - 格拉斯哥宣言 - 減少 90% 慢性 BC 肝炎的新病例減少 65% 慢性 BC 肝炎的死亡數讓 BC 肝炎且適合治療者治療率達到 80%