Send letter to journal:
Re: Re: Do baseline ALT levels predict complications of chronic hepatitis B?

Dear Editor We would like to thank Dr Huo and his colleagues for their comments. The followings are point-by-point responses to their comments.

1) The serum ALT levels were not considered in our analysis of prognostic factors because the stratification into 5 groups rendered it too complicated for statistical calculation of multivariate analysis. In addition, we aimed to examine independently the differences of the outcome in patients with different ALT since elevated ALT level is the most commonly used criterion for initiation of treatment [1]. As for HBV DNA levels, our conclusion was that development of cirrhosis complication was related to prolonged low level viremia up to the time of development of complications. Baseline HBV DNA levels would be of little help in determining whether HBV DNA levels were of importance. A good example would be the high HBV DNA levels in children; that does not mean they are at risk for cirrhotic complication when they are young.

2) We are not sure what Dr. Huo means. As is clearly shown in the table under Figure 2, for patients with ALT > 2 – 6 times upper limit of normal (ULN), the risk for development of complications was significantly different from those with ALT 0.5 – 1 X ULN. Also the risk for development of complications was significant LOWER than patients with ALT > 1 -2 X ULN and ALT > 2 – 6 X ULN. Clearly ALT levels of > 1-2 X ULN are at the highest risk for complications. We would like to stress “baseline HBV DNA levels” of the study of Yu et al were arbitrary [2], taken at the particularly time point the subjects were recruited on a completely random basis. As for the study of Yang et al. [3], the HBeAg status was only checked on recruitment. It is unknown what proportion of these patients had HBeAg seroconversion during subsequent follow-up of 92,359 patient-years, i.e., the HBeAg/ anti-HBe status was unknown at the time of development of hepatocellular carcinoma.

3) As for our specifically studying the late complications of cirrhosis, not only is this not a flaw, we consider this as one of the important and innovative aspect of our study. Dr. Huo is WRONG to say that only the formation of cirrhosis or hepatocellular carcinoma is directly linked with chronic HBV infection. As the study of Liaw et al has elegantly shown, lowering viral replication can suppress the DEVOLOPMENT of late complications of cirrhosis [4]. In fact, this exactly confirms the proposal of our study.

Man-Fung Yuen, MD, PhD
Ching-Lung Lai, MD
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Tel: 852 28554252
Fax: 852 28162863
Email: mfyuen{at}hkucc.hku.hk; hrmelcl{at}hkucc.hku.hk

References

1. Yuen MF, Yuan HJ, Wong DKH, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005;54:1610- 4.

2. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005;97:265-72.

3. Yang HI, Lu SN, Liaw YF, et al; the Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. New Engl J Med 2002;347:168-74.

4. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521-31.

Send letter to journal:
Re: Do baseline ALT levels predict complications of chronic hepatitis B?

Dear Editor,

We read with interest the paper by Yuen et al. published in a recent issue of Gut.[1] This study included a large patient cohort with chronic hepatitis B and analyzed the determinants predicting the outcome. Authors concluded that low level viremia and mildly elevated serum ALT levels more commonly lead to the development of complications. This conclusion, however, is not supported by their findings as the independent predictive factors are male gender, age, stigmata of chronic liver disease and others, whereas serum ALT and hepatitis B virus (HBV) DNA levels are not.

It is questionable if patients with mildly elevated baseline ALT levels are truly associated with a higher risk of complication. As shown in Fig. 2 in the paper,[1] the incidence of complication in group with ALT>2-6 x ULN and group with ALT>6 x ULN was still significantly higher compared to the group with ALT<0.5x ULN that had the lowest risk of complication. More importantly, serum ALT level was not an independent risk factor predicting a poor outcome in the Cox multivariate analysis, suggesting lower serum ALT and/or HBV DNA levels were only associated but not independent factors. Although HBV DNA levels were tested to correlate with the clinical course, it should be noted that DNA levels were measured at different time points (21 patients before, 9 at, and 80 after the complication developed) and this inhomogeneous information makes the analysis of the impact of HBV DNA level on disease course less useful. Interestingly, entirely different conclusions were reported from a recent study that prospectively investigated 4,841 Taiwanese men who were HBV carriers.[2] A higher baseline HBV DNA level was associated with an increased risk of the development of hepatocellular carcinoma (HCC) with a risk ratio up to 7.3-fold.[2] In addition, a positive baseline hepatitis B e antigen consistently predicted a higher risk of HCC.[2,3] The contrast between these studies can be best explained that patient data were collected at different time points in the natural history of chronic hepatitis B. In this regard, the necessity of serial multiple measurements of clinical parameters in patients with chronic hepatitis B has been emphasized to reveal important information associated long-term outcome.[4]

Another potential flaw in this study is that authors have defined ascites, spontaneous bacterial peritonitis and encephalopathy as complications of chronic hepatitis B. It should be noted these are rather late complications of cirrhosis and may not be directly related to HBV infection. Since the time interval from silent cirrhosis to the development of complication may vary widely and many cirrhotic patients never develop significant cirrhosis-related complications in the natural history, the complication should be defined as formation of cirrhosis or HCC which is directly linked with chronic HBV infection.

In summary, the evaluation of end point should be cirrhosis or HCC rather than cirrhosis-related complication which is not directly related to HBV infection. Lower serum ALT and HBV DNA levels more likely reflect a later stage of chronic hepatitis B and are possibly associated with increasing age of these patients who may already have severe fibrosis or sub-clinical cirrhosis.

Teh-Ia Huo, MD
Taipei Veterans General Hospital and National Yang-Ming University,
School of Medicine, Taipei, Taiwan

Correspondence to:
Teh-Ia Huo, MD
Division of Gastroenterology
Department of Medicine
Taipei Veterans General Hospital
Taipei, Taiwan
Tel: + 886 2 2871 2121 Ext.: 3352
Fax: + 886 2 2873 9318
Email: tihuo{at}vghtpe.gov.tw

Competing Interest: None declared.

References

1. Yuen MF, Yuan HJ, Wong DKH, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005;54:1610- 4.

2. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005;97:265-72.

3. Yang HI, Lu SN, Liaw YF, et al; the Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. New Engl J Med 2002;347:168-74.