慢性C型肝炎患者抗核抗體(ANA)陽性率對臨床表徵及對干擾素合併ribavirin治療療效之影響

The influence of seropositivity for antinuclear antibodies (ANA) on clinical manifestation and response to antiviral therapy for chronic hepatitis C patients

謝明彥(Ming-Yen Hsieh)

指導教授 ： 張文宇

共同指導教授 ： 莊萬龍(Wan-Long Chuang)

高雄醫學大學/醫學院/醫學研究所/碩士(2007年)

https://doi.org/10.6832/KMU.2007.00063

摘要

研究目的︰許多慢性C型肝炎患者的血清可以檢出陽性的抗核抗體 (ANA)。本研究評估台灣慢性C型肝炎患者ANA的盛行率，並且確認ANA與慢性C型肝炎在臨床上、病毒學，與病程等特性間的關聯性。本前瞻性研究同時評估ANA陽性對慢性C型肝炎患者接受長效型干擾素合併ribavirin抗病毒治療之影響。
研究方法︰本研究總共納入614位持續發病的慢性C型肝炎患者，並且予以測定C型肝炎病毒的基因型與RNA濃度。其中有243位不同時段納入的慢性C型肝炎病患接受peginterferon (PEG-IFN) α-2b或PEG-IFNα-2a 合併ribavirin治療24週，治療後持續追蹤24週。
結果︰614位慢性C型肝炎患者的血清ANA陽性盛行率(titer > 1:40)為35.0%。女性比男性明顯有較高的ANA陽性率(41.2% 比31.0%, p = 0.012)。檢出ANA陽性的患者普遍都較年長(mean 53.7 ± 10.5 vs. 49.7 ± 11.3 y, P < 0.001)，並且比未有ANA的患者呈現較高的胺基丙酸胺基轉移酶(ALT)平均值(186.9 ± 178.8 比155.50 ± 113.5 IU/L, p < 0.001)及較低的C型肝炎病毒RNA平均值(5.2 ± 0.9 vs. 5.4 ± 1.0 log IU/mL, p = 0.048)。當針對447名患者進行肝臟組織切片檢查後發現，與ANA陰性的患者比較起來，ANA陽性之患者有明顯較高的纖維化指數平均值(2.0 ± 1.3 vs. 1.5 ± 1.1, p <0.001)與較高的F3及F4期肝纖維化發生頻率(69/187, 36.9% vs. 50/260, 19.2%, p <0.001)。較嚴重的組織纖維化、較低的C型肝炎病毒RNA濃度，與年齡較大都是與ANA陽性有關聯的獨立因子。
243位接受合併治療24週之慢性C型肝炎病患中有187位(佔總人數的77%)達到治療之病毒持續反應(SVR)。在105位C型肝炎病毒基因型非第一型病患中；ANA陰性的患者比起ANA陽性的患者有較高之治療病毒持續反應(SVR)率(95.8%：67.7%, p = 0.013)。然而，138位C型肝炎病毒基因型第一型病患中，ANA陰性的患者和ANA陽性的患者之治療病毒持續反應(SVR)率無顯著差異。對C型肝炎病毒基因型非第一型病患而言，ANA陽性與否；年齡；C型肝炎病毒RNA濃度，為影響治療病毒持續反應(SVR)之相關獨立因子。對C型肝炎病毒基因型第一型病患而言，C型肝炎病毒RNA濃度；肝臟纖維化的嚴重程度，則是影響治療病毒持續反應(SVR)之相關獨立因子。
結論︰慢性C型肝炎患者有三分之一以上為ANA陽性， ANA陽性與疾病的臨床和病毒學特性有關。PEG-IFN/ribavirin的合併治療對於ANA陽性的C型肝炎病患治療成果極佳且安全。然而，對於對C型肝炎病毒基因型非第一型病患而言，ANA陽性濃度較高為預測治療無反應之獨立因子。

關鍵字

C型肝炎 ； 抗核抗體 ； 干擾素 ； 合併治療

並列摘要

Background: Positive serum antinuclear antibody (ANA) emerges in some proportion of patients with chronic hepatitis C virus (HCV) infection. This study aimed to evaluate the prevalence of ANA in chronic hepatitis C (CHC) patients and to elucidate its clinical implication in the virologic and histologic characteristics. This prospective study also evaluated the impact of ANA on the response to combined antiviral treatment in CHC patients.
Methods: Total 614 CHC patients were enrolled in this prospective, hospital-based study. Amongst those enrolled patients, 243 consecutive patients received either peginterferon (PEG-IFN) α-2b or PEG-IFNα-2a plus ribavirin for 24 weeks and were monitored for a further 24 weeks after the treatment ended. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), ANA, HCV genotypes, HCV RNA levels and histologic activity index (HAI) scores for liver histopathology were determined.
Results: The prevalence of positive ANA (titer > 1:40) was 35.0%. Women had a significantly higher prevalence than men (41.2% vs. 31.0%, p = 0.012). Patients with positive ANA were significantly older (mean 53.7 ± 10.5 vs. 49.7 ± 11.3 yrs, p < 0.001) and had higher mean ALT levels (186.9 ± 178.8 vs. 155.50 ± 113.5 IU/L, p < 0.001) and lower mean HCV RNA levels (5.2 ± 0.9 vs. 5.4 ± 1.0 log IU/mL, p = 0.048) than those without. Amongst 447 patients receiving liver biopsy, those with positive ANA significantly had a higher mean fibrosis score (2.0 ± 1.3 vs. 1.5 ± 1.1, p < 0.001) and a higher frequency of F3-4 (69/187, 36.9% vs. 50/260, 19.2%, p < 0.001) than those without. Multivariate logistic regression analyses showed that advanced fibrosis, lower HCV RNA levels, and age were significant factors related to positive ANA. Amongst those 243 patients who received antiviral therapy, 187 (77.0%) patients showed a sustained virological response (SVR) to treatment. In the 105 patients with HCV-non 1 infection, those who were negative for ANA had significantly higher SVR rate (95.8% vs. 67.7%, p = 0.013) compared to those positive for ANA. On the contrast, in the 138 patients with HCV-1 infection, there was no significant difference in SVR rate between patients with negative or positive ANA. ANA seropositivity, age and HCV RNA levels were independent factors related to SVR in patients with HCV-non 1 infection. HCV RNA levels and severity of fibrosis were independent factors related to SVR in patients with HCV-1 infection.
Conclusion: ANA is associated with a more advanced liver fibrosis and lower serum HCV RNA levels in CHC patients. PEG-IFN/ribavirin combination therapy is effective and safe in ANA-positive patients with CHC. High titer of ANA is predictive of nonresponse in patients with HCV-non 1 infection.

並列關鍵字

Hepatitis C virus ； antinuclear antibody ； interferon ； combination antiviral treatment

參考文獻

1.Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber MA, Sampliner RE, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992, 327(27):1899-1905.

2.Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. J Hepatol 1999, 31 Suppl 1:39-42.

3.McMurray RW, Elbourne K. Hepatitis C virus infection and autoimmunity. Semin Arthritis Rheum 1997, 26(4):689-701.

4.Zauli D, Cassani F, Bianchi FB. Auto-antibodies in hepatitis C. Biomed Pharmacother 1999, 53(5-6):234-241.

5.Clifford BD, Donahue D, Smith L, Cable E, Luttig B, Manns M, Bonkovsky HL. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995, 21(3):613-619.