Questions about Phases for the Natural History of HBV

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The Natural History of Chronic Hepatitis B Virus Infection  
By B. J. McMahon from HEPATOLOGY, Vol. 49, No. 5, Suppl., 2009

Chronic hepatitis B virus (HBV) infection has a complicated course. Three phases are

identified: an immune tolerant phase with high HBV DNA and normal alanine aminotransferase

(ALT) levels associated with minimal liver disease; an immune active phase with high

HBV DNA and elevated ALT levels with active liver inflammation; and an inactive phase

with HBV DNA levels < 2000 IU/mL and normal ALT levels with minimal inflammation

and fibrosis on liver biopsy. Affected persons can move progressively from one phase to the

next and may revert backward. The primary adverse outcomes of chronic HBV infection are

hepatocellular carcinoma (HCC) and cirrhosis. Published natural history studies were reviewed

and ranked by the strength of evidence regarding the study design. Factors with the

highest evidence of risk for development of HCC or cirrhosis from population-based prospective

cohort studies include male sex, family history of HCC, HBV DNA level above 2000

IU/mL in persons above age 40, HBV genotypes C and F, and basal core promoter mutation.

Those with the next highest level of evidence include aflatoxin exposure, and heavy alcohol

and tobacco use. Improved methods to identify persons at highest risk of developingHCCor

cirrhosis are needed to allow intervention earlier with antiviral therapy in appropriate

patients. Future studies should include prospective follow-up of established populationbased

cohorts as well as new cohorts recruited from multiple centers stratified by HBV

genotypes/subgenotypes and clinical phase to determine the incidence of the various HBV

phases, HCC, and cirrhosis. Also, nested case-control studies assessing immunological and

host genetic factors among persons with active and inactive disease phases, HCC, and

cirrhosis could be conducted using these types of cohorts.

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这是一篇较老的文章，估计很多人熟知，是制定中外指南的一个依据。但文中的主要结论是根据数据分析得到的，对其背后的生化原因解析不详，我有几点疑问，望得到指点：1. 文中把HBV感染分成3阶段
     1.
immune tolerant phase with high HBV DNA and normal alanine aminotransferase
(ALT) levels associated with minimal liver disease; 免疫耐受阶段，此阶段特点是高载量HBVDNA和正常的ALT和很轻的肝脏疾病
      2. an immune active phase with high HBV DNA and elevated ALT levels with active liver inflammation;
           免疫激活阶段，特点是高载量HBVDNA，升高的ALT和肝脏炎症。
      3. an inactive phase  with HBV DNA levels < 2000 IU/mL and normal ALT levels with minimal inflammation

and fibrosis on liver biopsy.

           静止阶段，HBVDNA <2000IU/ml(~1e5 copies/ml) 正常的ALT和很轻的肝脏炎症和纤维化。

问题：

     为什么免疫激活阶段会有高载量的HBVDNA？HBVDNA高是激活免疫和引起肝损伤的一个因数？如何解析HBVDNA低但肝功不正常的情况？

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文中还提到了肝细胞癌和肝硬化的高危因素：

1.男性

2. 肝癌家族史

3. HBVDNA>2000 IU/ml.

4. 年龄>40

5. HBV 基因型 C/F

6. basal core promoter mutation(基本核心启动子？变异)

“Factors with the highest evidence of risk for development of HCC or cirrhosis from population-based prospective cohort studies include male sex, family history of HCC, HBV DNA level above 2000

IU/mL in persons above age 40, HBV genotypes C and F, and basal core promoter mutation.”

文中还指出黄曲霉素，烟酒的危险性

“Those with the next highest level of evidence include aflatoxin exposure, and heavy alcoholand tobacco use”

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文中还有这一段指出免疫耐受的潜在风险
“During this phase, there is either no or minimal liver
inflammation or fibrosis. However, because the HBV
polymerase gene has reverse transcriptase properties,HBV integrates randomly into the host’s hepatocyte DNA and during the immune tolerant phase, persistently
high levels of HBV DNA over many years would likely
mean an accumulation of integration sites, increasing the
risk of HCC over time even in the absence of active liver
inflammation and fibrosis.”
“在这个（免疫）阶段，肝脏没有或只有很轻的炎症合纤维化。但是由于HBV聚合酶的逆转录特性，
HBV会随机地整合到肝细胞的DNA中，在免疫耐受期持续多年的HBV DNA高载量有可能意味着整合了HBVDNA的肝细胞的积聚，从而导致肝细胞癌的风险的增加，即使没有肝脏的炎症和纤维化”




这个似乎与广泛接受的耐受期无需治疗的观点不符。一般的说法肝硬化会导致肝癌风险的大大增加。但是否有数据说明HBV多年携带没有肝硬化的肝癌发生率，是否有数据揭示携带时间和肝癌风险的关系

StephenW

Vitamins 发表于 2011-7-23 07:45
回复 Vitamins 的帖子

这是一篇较老的文章，估计很多人熟知，是制定中外指南的一个依据。但文中的主要结论 ...

我会给你我的意见，如果我错了,其他人可以纠正我.

问题：

     为什么免疫激活阶段会有高载量的HBVDNA？HBVDNA高是激活免疫和引起肝损伤的一个因数？

如果没有我们的免疫系统和药物，HBVDNA将永远是高的。

当我们的免疫系统激活，它会尝试清除病毒感染的肝细胞，在这个过程中，它会破坏一些受感染的肝细胞。

如何解析HBVDNA低但肝功不正常的情况？

它可以是由于其他因素，如：
1。脂肪肝的
2。其他肝脏疾病。

ALT下降速度可能不会为HBVDNA下降速度快。
医生们喜欢用的一句话：持续(persistently), 因此，我们不应该依赖于一个单一的结果，但依靠趋势(trend)和其他指标

StephenW

Vitamins 发表于 2011-7-23 08:59
文中还有这一段指出免疫耐受的潜在风险
“During this phase, there is either no or minimal liver
inflam ...

这个似乎与广泛接受的耐受期无需治疗的观点不符。一般的说法肝硬化会导致肝癌风险的大大增加。但是否有数据说明HBV多年携带没有肝硬化的肝癌发生率，是否有数据揭示携带时间和肝癌风险的关系
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有两种风险：
1。由于肝硬化（病毒，大量饮酒和其他肝脏疾病,等等）
2。病毒基因与人类基因相结合，引起基因的突变导致癌症.

"无需治疗的观点不符" - 更重要的是，没有治疗治愈。因此，是一个平衡的问题。如果有一个治疗治愈乙肝，当然，儿童也应治疗！

alex1234

Vitamins 发表于 2011-7-23 08:59
文中还有这一段指出免疫耐受的潜在风险
“During this phase, there is either no or minimal liver
inflam ...

HBV DNA整合目前还是有争议的，一些人认为这只是实验室的玩笑而已。