慢性乙型肝炎的灰色地带：治疗还是不治疗

StephenW

The Gray Zone of Chronic Hepatitis B: To Treat or Not to Treat
                

Mindie H. Nguyen, MD, MAS, AGAF, FAASLD
Professor of Medicine
Department of Gastroenterology and Hepatology
Stanford University Medical Center
Palo Alto, California

Hepatitis B is a complex disease, and some of the basics of when and how to treat patients with chronic HBV infection are not always straightforward. I find that one of the most difficult aspects of managing patients with chronic hepatitis B (CHB) is distinguishing patients who have active disease, requiring intervention or more intensive monitoring, from patients who have inactive disease, requiring only standard monitoring without treatment. The complexity comes in part from the definition of a normal ALT level, which is used to assess liver inflammation, and from what constitutes a high HBV DNA level. We use these parameters to categorize our patients for optimal clinical management.

ALT and HBV DNA Thresholds
The American Association for the Study of Liver Diseases (AASLD) practice guidance recommends treatment for patients with ALT levels ≥ 2 x the upper limit of normal (ULN) (where normal is defined as 25 U/mL for women and 35 U/mL for men) and HBV DNA > 20,000 IU/mL for patients with HBeAg-positive CHB or HBV DNA ≥ 2000 IU/mL for patients with HBeAg-negative CHB. However, there are many patients whose elevated ALT levels do not quite reach ≥ 2 x ULN, but who are at risk for hepatocellular carcinoma or cirrhosis and could benefit from more intervention. In addition, HBV DNA levels should be considered in the context of other risk characteristics such as age, sex, duration of infection, and family history. For example, being male or older increases the risk of hepatocellular carcinoma. It is important to understand that the AASLD guidelines do not say that anyone with ALT < 2 x ULN does not need treatment. Instead, the guidelines allow clinicians to consider multiple factors, and some patients fall into the gray zone not clearly defined by the guidelines.  

Patients With Fluctuating ALT Levels
One group of patients I often encounter in my practice whose management is not clearly outlined in the guidelines are patients with fluctuating ALT levels. Because ALT monitoring is done every 3-6 months, it is possible to miss ALT elevations that occur between testing intervals. Given that CHB is a very dynamic disease, having a normal ALT in June does not mean that the ALT will be normal in August. In my practice, I would consider a patient with an ALT that has fluctuated more than once during a 1-year to 2-year period to have active disease and would consider therapeutic intervention for that patient.

Immune-Tolerant CHB
Another group of gray zone patients are those with high HBV DNA levels but persistently normal ALT, known as immune-tolerant CHB. In some cases, these patients are truly immune tolerant with no active liver disease. The current AASLD practice guidance states that these patients do not warrant treatment. However, does this patient have no risk at all? Once again you must consider their age, sex, family history, and other factors that may place them at higher risk of poor outcomes. The guidance notes that a liver biopsy should be considered in patients with persistently borderline normal or slightly elevated ALT levels, particularly those who have been infected with HBV for a long period of time and are now older than 40 years of age. Patients with moderate to severe inflammation and/or fibrosis can be considered for treatment, even with borderline normal or slightly elevated ALT levels. At this time, I generally do not treat patients with a persistently normal ALT.

Your Thoughts
Do you consider factors other than ALT and HBV DNA levels when deciding if a patient should be treated for CHB? Please elaborate in the comments section.

StephenW

慢性乙型肝炎的灰色地带：治疗还是不治疗

Mindie H. Nguyen医学博士，MAS，AGAF，FAASLD
医学教授
消化内科
斯坦福大学医学中心
加利福尼亚帕洛阿尔托

乙型肝炎是一种复杂的疾病，何时以及如何治疗慢性HBV感染患者的一些基本知识并不总是那么简单。我发现管理慢性乙型肝炎（CHB）患者最困难的方面之一是将患有活动性疾病，需要干预或需要更深入监测的患者与没有活动性疾病，仅需要标准监测而无需治疗的患者区分开。复杂性部分来自正常ALT水平的定义（用于评估肝脏炎症），以及高HBV DNA水平的构成。我们使用这些参数对患者进行分类，以实现最佳临床管理。

ALT和HBV DNA阈值
美国肝病研究协会（AASLD）实践指南建议对ALT水平≥2倍于正常上限（ULN）的患者进行治疗（正常情况下，女性的定义为25 U / mL，而正常的定义为35 U / mL）。男性），HBeAg阳性CHB患者的HBV DNA> 20,000 IU / mL，HBeAg阴性CHB患者的HBV DNA≥2000 IU / mL。但是，许多患者的ALT水平升高并没有达到≥2 x ULN，但是有患肝细胞癌或肝硬化的风险，可以从更多干预中受益。此外，应在其他风险特征（例如年龄，性别，感染持续时间和家族史）的背景下考虑HBV DNA水平。例如，年龄较大的男性会增加患肝细胞癌的风险。重要的是要了解，AASLD指南并没有说ALT <2 x ULN的任何人都不需要治疗。取而代之的是，该准则允许临床医生考虑多种因素，并且一些患者陷入准则未明确定义的灰色区域。

ALT水平波动的患者
我在实践中经常遇到的一组患者的治疗方法未在指南中明确列出，而这些患者的ALT水平却波动不定。由于ALT监测每3-6个月进行一次，因此有可能会错过测试间隔之间发生的ALT升高。鉴于CHB是一种非常动态的疾病，因此6月的ALT正常并不意味着8月的ALT正常。在我的实践中，我将考虑一名ALT在1年至2年内波动超过一次的患者患有活动性疾病，并考虑对该患者进行治疗性干预。

免疫耐受CHB
另一组灰区患者是那些HBV DNA水平高但ALT持续正常的患者，称为免疫耐受性CHB。在某些情况下，这些患者真正具有免疫耐受性，没有活动性肝病。当前的AASLD实践指南指出，这些患者不需接受治疗。但是，该患者完全没有风险吗？再一次，您必须考虑他们的年龄，性别，家族史以及其他可能使他们面临不良结局风险的更高因素。该指南指出，对于ALT水平持续稳定或持续升高的患者，应考虑进行肝活检，尤其是长期感染HBV且年龄超过40岁的患者。中度至重度炎症和/或纤维化的患者，即使ALT水平处于正常水平或略有升高，也可以考虑进行治疗。目前，我通常不治疗ALT持续正常的患者。

你的意见
在决定是否应该对CHB进行治疗时，您是否考虑了ALT和HBV DNA水平以外的因素？请在评论部分中详细说明。