Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time

Abstract

The baseline alanine aminotransferase (ALT) level was reported to have prognostic value in chronic hepatitis B virus (HBV) infection, during which ALT may change over time. Instead of baseline ALT, this study aimed to study the prognostic value of the height of ALT during the course of chronic HBV infection. A total of 4376 asymptomatic hepatitis B e antigen (HBeAg) negative, surface antigen (HBsAg) carriers with baseline ALT less than 2 times the upper limit of normal (ULN) were monitored with ALT measurement and ultrasonography every 3 to 12 month for over 3 years. Maximal ALT levels during follow-up were correlated with long-term outcomes using morbidity and mortality data from hospital records, cancer registration, and national mortality database. Baseline ALT level was normal in 3673 subjects and increased to abnormal level in 1720 (46.8%) during a mean follow-up period of 13.4 ؎ 5.2 (3.0-28.7) years. The incidence of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality increased with increasing maximal ALT level during follow-up, especially in those with maximal ALT of at least 2 times ULN, as compared with those who maintained normal ALT. Cox regression analysis indicated that age at entry, sex, and maximal ALT level during follow-up were significant independent factors associated with the development of cirrhosis, HCC, and mortality whereas cirrhosis was also an independent factor for HCC development and mortality. Conclusion: Persistently normal ALT was associated with excellent long-term prognosis, whereas increasing ALT levels of at least 2 times ULN during follow-up was associated with increasing morbidity and mortality. ALT of at least 2 times ULN is therefore an appropriate threshold for anti-HBV therapy, whereas those with ALT 1 to 2 times ULN require liver biopsy for decision. (HEPATOLOGY 2009;49: 1859-1867.) C hronic hepatitis B virus (HBV) infection is one of the major causes of liver morbidity and mortality. 1,2 Recent community-based studies involving a large number of hepatitis B surface antigen (HBsAg) positive subjects, mainly (Ͼ85%) hepatitis B e antigen (HBeAg) negative, have shown that baseline age, sex, HBeAg serostatus, and serum HBV-DNA level are factors associated with hepatocellular carcinoma (HCC) development and liver-related mortality. 3,4 Abnormal alanine aminotransferase (ALT) at entry was also found to be associated with cirrhosis development and liver-related mortality. 5,6 All HBV treatment guidelines of major liver associations also recommend that patients with active HBV replication and an ALT level greater than 2 times Abbreviations: AFP, alpha-fetoprotein; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; maxALT, maximal alanine aminotransferase; PNALT, persistently normal alanine aminotransferase; ULN, upper limit of normal; US, ultrasonography.

Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads

“…6,9,11 In fact, ample evidence has shown that viral load is transiently suppressed when hepatitis activity occurs. 22 Because our primary criterion for enrollment was HBeAg-negative status with an HBV DNA level <2,000 IU/mL, we believe that some of the study participants, especially those with elevated ALT levels, were not really at an inactive state but had transient viral suppression.…”

“…11,14,16,17 Detection of liver cirrhosis via abdominal ultrasonography was performed according to a scoring system based on the features of liver parenchyma, liver surface, hepatic vessel, and spleen size. For ultrasonographic diagnosis of cirrhosis to be made, the score had to be !8 on at least two ultrasonographic studies more than 6 months apart.…”

“…9 Nevertheless, the underlying mechanisms remain unclear and warrant further investigation.It is generally believed that, in HBV carriers, cirrhosis usually results from the accumulation of extracellular matrix from liver cell injury, and HCC may subsequently emerge in the setting of cirrhosis. 10,11 The major driving force of all these adverse events has been shown to be serum HBV DNA level. [5][6][7] However, HBV DNA level fluctuates easily, whereas HBsAg level remains relatively stable.…”

Interpretation US Elastography in Chronic Hepatitis B with or without Anti-HBV Therapy

“…Liver cirrhosis is the major risk factor for mortality in chronic hepatitis B carriers [1,2]. The annual rate of progression from chronic hepatitis to cirrhosis is 2-5% in hepatitis B e antigen-positive and 3-10% in e antigen-negative patients [3,4].…”

“…The diagnosis and further therapeutic decision usually relies on the fibrosis severity, so an accurate assessment is crucial to treatment outcomes. It is easy to diagnose cirrhosis by liver ultrasound [1,2]-what is more difficult is assessing more subtle degrees of fibrosis. Liver biopsy is considered the gold standard for liver fibrosis assessment; however, it is an invasive procedure with rare, but serious complications (mortality rate < 0.01%) [6].…”