The clinical significance of persistently normal ALT in chronic hepatitis B infection q Michelle Lai, Benjamin J. Hyatt, Imad Nasser, Michael Curry, Nezam H. Afdhal * Beth Israel Deaconess Medical Center, Division of Hepatology, Harvard Medical School, Boston, MA, USA Background/ Aims: Chronic hepatitis B virus (HBV) disease is caused by both necroinflammation and active viral repli- cation. The role of ALT levels as a predictor of liver injury has recently been questioned. The aim of the study was to determine whether normal ALT is associated with liver injury in a cohort of HBV patients undergoing liver biopsy. Methods: This is a retrospective review of chronic HBV patients divided into 3 groups; (1) persistently normal ALT (PNALT); (2) ALT 1–1.5X ULN and (3) ALT > 1.5X ULN. Multiple clinical, biochemical, virological variables were evaluated. Results: One hundred and ninety-two patients met the inclusion criteria, 59 with PNALT, 26 with ALT 1–1.5X ULN, and 107 with ALT > 1.5X ULN. Increasing age, higher ALT, higher grade of inflammation on biopsy, and HBeAg pos- itivity predicted fibrosis. 18% of patients with PNALT had stage 2+ fibrosis and 34% had grade 2 or 3 inflammation. Overall 37% of patients with PNALT had significant fibrosis or inflammation. Subgroup analysis showed the majority with fibrosis belonged to the high normal ALT group and that only a minority who were young and immune tolerant had sig- nificant findings on biopsy. Conclusions: There is significant fibrosis and inflammation in 37% of patients with PNALT and a liver biopsy should be considered in patients older than 40 with high normal ALT. Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Liver biopsy; Fibrosis; Normal ALT; Hepatitis B 1. Introduction Hepatitis B virus (HBV) infection is a serious public health problem with more than 350 million people esti- mated to be chronically infected worldwide, of whom one million die annually from HBV-related liver disease [1]. Chronic hepatitis B develops in 90% of newborns infected with HBV, approximately 30% of infants, and less than 5% of immunocompetent adults [2]. Death from chronic liver disease occurs in 15–25% of chroni- cally infected persons [3]. In chronic hepatitis B infection, chronic inflammation can lead to an increasing degree of fibrosis and ulti- mately cirrhosis and its complications. Chronic hepatitis B is a common cause of cirrhosis in the United States and is an important cause of liver cancer [2]. The five- year rate of progression from chronic hepatitis B to cir- rhosis is estimated to be 12–20% [4–6]. However, disease progression is variable and not everyone with chronic hepatitis B infection progresses to severe fibrosis or cirrhosis. The rate of progression to cirrhosis is influenced by the degree of inflammation which, in turn, is determined by factors such as the rep- licative activity of the virus, superinfection by hepatitis delta virus (HDV), and concurrent liver injury from other causes [2]. More recently the level of HBV DNA at baseline has also been associated with progression 0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.07.022 Received 27 March 2007; received in revised form 2 July 2007; accepted 16 July 2007; available online 24 September 2007 Associate Editor: G.K.K. Lau q The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manu- script. * Corresponding author. Tel.: +1 617 632 1069; fax: +1 617 632 1054. E-mail address: [email protected](N.H. Afdhal). www.elsevier.com/locate/jhep Journal of Hepatology 47 (2007) 760–767
Transcript
www.elsevier.com/locate/jhep
Journal of Hepatology 47 (2007) 760–767
The clinical significance of persistently normal ALTin chronic hepatitis B infectionq
Michelle Lai, Benjamin J. Hyatt, Imad Nasser, Michael Curry, Nezam H. Afdhal*
Beth Israel Deaconess Medical Center, Division of Hepatology, Harvard Medical School, Boston, MA, USA
Background/Aims: Chronic hepatitis B virus (HBV) disease is caused by both necroinflammation and active viral repli-
cation. The role of ALT levels as a predictor of liver injury has recently been questioned. The aim of the study was to
determine whether normal ALT is associated with liver injury in a cohort of HBV patients undergoing liver biopsy.
Methods: This is a retrospective review of chronic HBV patients divided into 3 groups; (1) persistently normal ALT
(PNALT); (2) ALT 1–1.5X ULN and (3) ALT > 1.5X ULN. Multiple clinical, biochemical, virological variables were
evaluated.Results: One hundred and ninety-two patients met the inclusion criteria, 59 with PNALT, 26 with ALT 1–1.5X ULN,
and 107 with ALT > 1.5X ULN. Increasing age, higher ALT, higher grade of inflammation on biopsy, and HBeAg pos-
itivity predicted fibrosis. 18% of patients with PNALT had stage 2+ fibrosis and 34% had grade 2 or 3 inflammation.
Overall 37% of patients with PNALT had significant fibrosis or inflammation. Subgroup analysis showed the majority with
fibrosis belonged to the high normal ALT group and that only a minority who were young and immune tolerant had sig-
nificant findings on biopsy.
Conclusions: There is significant fibrosis and inflammation in 37% of patients with PNALT and a liver biopsy should be
considered in patients older than 40 with high normal ALT.� 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Liver biopsy; Fibrosis; Normal ALT; Hepatitis B
1. Introduction
Hepatitis B virus (HBV) infection is a serious publichealth problem with more than 350 million people esti-mated to be chronically infected worldwide, of whomone million die annually from HBV-related liver disease[1]. Chronic hepatitis B develops in 90% of newbornsinfected with HBV, approximately 30% of infants, andless than 5% of immunocompetent adults [2]. Death
0168-8278/$32.00 � 2007 European Association for the Study of the Liver.
doi:10.1016/j.jhep.2007.07.022
Received 27 March 2007; received in revised form 2 July 2007; accepted
16 July 2007; available online 24 September 2007
Associate Editor: G.K.K. Lauq The authors declare that they do not have anything to disclose
regarding funding or conflict of interest with respect to this manu-script.
from chronic liver disease occurs in 15–25% of chroni-cally infected persons [3].
In chronic hepatitis B infection, chronic inflammationcan lead to an increasing degree of fibrosis and ulti-mately cirrhosis and its complications. Chronic hepatitisB is a common cause of cirrhosis in the United Statesand is an important cause of liver cancer [2]. The five-year rate of progression from chronic hepatitis B to cir-rhosis is estimated to be 12–20% [4–6].
However, disease progression is variable and noteveryone with chronic hepatitis B infection progressesto severe fibrosis or cirrhosis. The rate of progressionto cirrhosis is influenced by the degree of inflammationwhich, in turn, is determined by factors such as the rep-licative activity of the virus, superinfection by hepatitisdelta virus (HDV), and concurrent liver injury fromother causes [2]. More recently the level of HBV DNAat baseline has also been associated with progression
M. Lai et al. / Journal of Hepatology 47 (2007) 760–767 761
to cirrhosis and HCC [7]. A persistent and importantquestion is whether patients with active viremia but nor-mal ALT can progress to liver disease.
We hypothesized that patients with persistently nor-mal ALT but active viral replication (HBV DNA >10,000 copies/mL) may have clinically significant histo-logical disease.
2. Materials and methods
We screened the charts of all patients seen in the Beth Israel Dea-coness Medical Center (BIDMC) Liver Center between the dates ofJanuary 1, 2000 and April 19, 2005 with the ICD-9 code of 070.32.This time period was chosen because it coincided with the clinical prac-tice guideline at BIDMC of biopsying all patients seen with HBVDNA > 10,000 copies/mL and was felt to exclude bias in biopsy deci-sion. We included patients with a positive hepatitis B surface antigen,HBV DNA > 10,000 copies/mL or equivalent, a liver biopsy or clinicalcirrhosis. For this study, clinical cirrhosis was defined as having eitherone of the following: ascites, esophageal varices, or encephalopathy; ortwo of the following: thrombocytopenia <130,000, hypoalbuminemia<3.5 mg/dL, portal hypertensive gastropathy, radiographic spleno-megaly, and radiographic nodular liver. Patients were excluded if theyhad hepatocellular carcinoma, immunosuppression, HIV, history ofpositive HCV RNA, hemachromatosis or other chronic liver diseasesor treatment with oral antiviral nucleosides or nucleotides therapyprior to biopsy, but included if their therapy was limited to interferonmore than 1 year prior to biopsy.
Data collected were age, sex, race, e antigen and antibody status,viral load, mode and date of transmission if known, all ALT andAST values known, weight, current or prior heavy alcohol use, co-
Fig. 1. Study
infection with HIV, HCV, or HDV, comorbidities, prior to interferontherapy, biopsy date, stage, grade, presence of steatosis and iron andbiopsy length. The date of the liver biopsy was used as the referencepoint with all data collected prior to biopsy. Liver biopsies were scoredusing the Metavir scoring system for both inflammation and fibrosis.Age was defined as age at biopsy. Prior or current heavy alcohol usewas defined as >50 g/day for 5 years or more.
The study protocol conformed to the ethical guidelines of the 1975Declaration of Helsinki as reflected in a priori approval by the BIDMCInstitutional Review Board. Since it was a retrospective chart reviewwith all identifying patient information removed, informed consentwas waived.
2.1. Statistical methods
Twenty-two patients had viral loads that were measured by non-PCR methods, given in picograms/mL, with the lower limits of detec-tion at 5 pg/mL. These values were converted to copies/mL using theconversion factor of 1 pg/mL = 283,000 copies/mL. Viral load in these22 patients ranged from 15 to 11,820 pg/mL with five viral loads notquantified above the upper limit of 2000 pg/mL. Values given as IU/mL were converted to copies/mL by multiplying by a factor of 5. Viralloads measured by PCR methods ranged from 10,000 to1,700,000,000 copies/mL, with multiple values not quantified abovedifferent upper limits which ranged from 200,000 to 500,000,000 cop-ies/mL. All analyses were done on log transformation of the viral load.Many of the viral loads were not quantified above the upper limit ofthe assays which limited significant analyses involving viral load. Forour analyses, the upper limit of the assay was used in these cases withan additional variable created to note that the viral load was notquantified.
Based on pre-biopsy ALT values, patients were classified into oneof three categories: normal ALT, ALT 1–1.5 times upper limits of nor-mal (ULN), and ALT > 1.5 times ULN. The maximal ALT level over
design.
762 M. Lai et al. / Journal of Hepatology 47 (2007) 760–767
at least a minimum of 6 months determined the group selection. Nor-mal ALT was defined by having at least two ALT values equal to orless than 40 IU/L at least six months apart and no elevated ALT atany time point prior to biopsy. The normal cutoff of 40 IU/L was usedby the BIDMC Laboratory for both men and women and for femaleadults by LabCorp and Quest Diagnostics. However, for male adults,it is 55 and 60 IU/L for LabCorp and Quest Diagnostics, respectively.Stage of fibrosis and grade of inflammation were also converted intobinomial variables of significant fibrosis (stage 2–4) vs. no significantfibrosis (stage 0–1) and significant inflammation (grade 2–3) vs. no sig-nificant inflammation (grade 0–1).
Univariate analyses, correlation matrices, v2 test, and multivariateregression analyses were performed using SAS statistical software 9.1for Windows. Multiple logistic regression analysis was performed toidentify predictors of significant fibrosis. The variables found to corre-late with stage in the correlation matrix and in univariate analysis wereincluded in the multivariate regression analysis.
Further subgroup analyses were performed. One stratified patientswith persistent normal ALT into low normal (ALT 0–25) and highnormal (ALT 26–40), which is consistent with the recommendationof normal ALT in males according to the new AASLD guidelinesfor HBV. The second subgroup analysis stratified the patients byHBeAg status. Distribution of stage and grade was also looked at insubgroups of high ALT patients. They were categorized into sub-groups of patients with median ALT value >1.5X ULN, >2XULN,>3XULN, or >5XULN.
3. Results
Of the 593 patients with an ICD-9 code of 070.32, 192patients met our inclusion and none of the exclusion crite-ria. Of these 192 patients, there were 59 patients with
a Significant difference between groups with p-value of 0.0011.b Significant difference between groups with p-value of <0.0075.c Significant difference between groups with p-value of <0.0001.d Significant difference between groups with p-value of <0.0001.e Viral loads not quantified above upper limits.f Some of the viral loads not quantified above upper limits.
PNALT, 26 patients with ALT 1–1.5X ULN, and 107patients with ALT > 1.5X ULN (see Fig. 1). Of the 59patients with normal ALT, 20 had a mean ALT 625 IU/L while 39 patients had a mean ALT level of 26–40 IU/L. Eight patients with clinical cirrhosis wereincluded without a liver biopsy. The number of patientsexcluded and the reasons for exclusions are shown inFig. 1.
Table 1 shows the demographic data. The normalALT group was predominantly female while those withelevated ALT were predominantly male (p < 0.0001).While the difference in age between the groups was notstatistically significant, there was a trend for normalALT group to include younger patients. Of the 25patients under age 40 with high viral load and normalALT, who represent probable immunotolerance, only3 had significant fibrosis. A higher ALT was associatedwith high alcohol intake but not with either HBV DNAlevel or HBeAg status.
Fig. 2 illustrates the stage and grade on liver biopsy inthe different ALT groups. Increasing ALT was associ-ated with more fibrosis and inflammation such that sig-nificant fibrosis (stage 2–4) was found in 18%, 34%, and62% of the patients in the normal ALT, ALT 1–1.5XULN, and ALT > 1.5X ULN group, respectively. Sig-nificant inflammation (grade 2–3) was seen in 34%,54% and 78% of the patients in the normal ALT, ALT
a Significant difference between groups with p-value of 0.0035.b Significant difference between groups with p-value of 0.03.c Viral loads not quantified above upper limits.d Some of the viral loads not quantified above upper limits.
M. Lai et al. / Journal of Hepatology 47 (2007) 760–767 763
1–1.5X ULN, and ALT > 1.5X ULN group, respec-tively. Overall 37% of patients in the normal ALT grouphad either significant inflammation or fibrosis.
4. Subgroup Analyses
Table 2 shows the characteristics of the normal ALTsubgroups. We found a significant disparity in gender,with the low normal group being 85% female and thehigh normal group 54% male (p < 0.0001). The racialbreakdown and age were similar. Though not statisti-cally significant, there was a trend for higher meanweight, stage and grade in the high normal group ascompared to the low normal group. There was also ahigher proportion of patients with steatosis in the highnormal patients. Log of viral load, history of alcoholuse, HBeAg status, and age were similar between thetwo subgroups.
Fig. 3 shows the distribution of stage and gradewithin each of the normal ALT subgroups. Significantfibrosis in the high normal group was five times as pre-
valent as in the low normal group (25% vs. 5%). Theprevalence of significant inflammation in the high nor-mal group (41%) was double that of the low normalgroup (20%). Overall 20% of patients with low normalALT had either significant inflammation or fibrosiscompared to 46% with high normal ALT.
Fig. 4 shows the distribution of stage and gradewithin each of the ALT groups including the highALT subgroups. The distribution of stage and gradewas not statistically significantly different between thedifferent high ALT subgroups.
Stratifying for HBeAg status revealed that anti-HBe+ patients were older, heavier and had lower viralload (Tables 3 and 4).
The correlation matrix revealed that increased fibro-sis was correlated with older age, more significantinflammation, higher ALT and male sex. Increasedinflammation was correlated with higher ALT. Olderand heavier patients were more likely to have steatosis.Asian-Americans and women had lower weight. Womenalso had lower ALT.
Given the association observed between many of thecovariates, multivariate logistic regression analysis wasperformed, controlling for all covariates simultaneously.The analysis revealed that increasing age, histologicalgrade and ALT group as well as HBeAg positivity aresignificant independent predictors of fibrosis (Table 5).Greater age and histological grade are the strongest pre-dictors of significant fibrosis (p = 0.0005 and <0.0001,
Fig. 3. Stage and grade by normal ALT subgroup (a). Stage by normal
ALT subgroup (b). Grade by normal ALT subgroup.
Fig. 4. (a) Distribution of stage by ALT group. (b) Distribution of grade
by ALT group.
764 M. Lai et al. / Journal of Hepatology 47 (2007) 760–767
respectively). Controlling for all other covariates, it wasrevealed that an increase in age by a decade approxi-mately doubles the risk of having significant fibrosis.An increase by one grade increases the risk of significantfibrosis by more than 6 times. Higher ALT andHBeAg+ are also significant predictors of significantfibrosis (p = 0.037 and 0.046, respectively). With move-ment from one ALT category to the next, one’s risk ofsignificant fibrosis is increased by 0.58 times. HBeAg+subjects are almost 3 times as likely to have significantfibrosis as subjects who are anti-HBe+.
Table 6 shows the results of the multiple logisticregression analysis performed after stratifying forHBeAg status. After stratification, older age and gradestill remained significant predictors of significant fibro-sis. In the HBeAg+ cohort, an increase in age by 10years doubled the risk of significant fibrosis (p = 0.017)while the risk was 2.5 times in the anti-HBe+ cohort(p = 0.016). With every increase in grade, there was a5.4 times increased risk of significant fibrosis in HBeAgpositive patients and 12.4 times increased risk of signif-icant fibrosis in anti-HBe+ patients. Increasing ALTwas a predictor of significant fibrosis and inflammation
in HBeAg+ patients but not in anti-HBe+ patients (OR1.767 and 1.885; p = 0.042 and 0.026, respectively). Sig-nificant alcohol use was found to be a predictor only inanti-HBe+ (OR 30.724; p = 0.033). Stage was a predic-tor of significant inflammation in the anti-HBe+ cohort(OR 10.171, p = 0.008).
5. Discussion
There is a major debate as to the appropriateapproach to the patient with HBV, active viremia andnormal ALT. Keefe et al. recommend individualizedcare and performance of a liver biopsy [8]. The newAASLD guidelines recommend the consideration ofliver biopsy and treatment in patients with persistentborderline normal or slightly elevated ALT levels, par-ticularly if the patient is above age 40 [9]. Our findingsof significant disease in 37% of PNALT patients suggest
Table 3
Study population characteristics by HBeAg status and ALT group
PNALT N (%) ALT 1–1.5 ULN N (%) ALT > 1.5 ULN N (%)
a Viral loads not quantified above upper limits.b Some of the viral loads not quantified above upper limits.
M. Lai et al. / Journal of Hepatology 47 (2007) 760–767 765
that some of the patients with persistent normal ALT >40 years should be considered for liver biopsy and treat-ment. Which of the PNALT patients should be biop-sied? Our subgroup analysis, which demonstrates that46% of patients with high normal ALT have significantdisease as compared to 20% of patients with low normalALT, would prompt liver biopsy in the high normal sub-group. This is consistent with the new AASLD guidelinesuggestion of lowering the upper limits of normal forALT and recent data from Lin et al. that correlate viro-logical parameters of progressive disease with high nor-mal ALT [10].
When classifying the clinical scenarios of HBV,immunotolerant patients are commonly defined asyoung, active viral replication (HBV DNA >105 cop-ies/mL, usually >108 copies/mL) with HBeAg+, butnormal ALT. Many of the normal ALT patients in thisstudy did not really meet the criteria for immunotoler-ance due to either older age or lower viral loads. Inthe 25 young immunotolerant patients, significant fibro-sis was only seen in only 3 patients. In a recent paper by
Andreani et al., no or minimal fibrosis was found in allof their immunotolerant patients [11]. We need to differ-entiate immunotolerance from normal ALT, and theterm immunotolerance should be reserved for youngpatients with HBV DNA >108 copies/mL and low nor-mal ALT (<25 IU).
In the normal ALT patients the decision to perform aliver biopsy should balance the cost and risks of liverbiopsy against the chance of not identifying patientswhose disease will progress without treatment. Withthe development on the horizon of non-invasive tech-niques of staging liver disease, the balance may swingtowards evaluating all HBV patients including thosewith normal ALT. In addition, even though we lookedat ALT over time, it is impossible to really knowwhether ALT is persistently normal for years or thatwe are seeing the product of flares of inflammation overtime. Clinical evaluation of HBV should always takeinto account duration of disease since persistent diseasewith viremia has been shown to be associated with riskof cirrhosis development irrespective of ALT level [7].
Table 4
Characteristics for normal ALT subgroups by HBeAg status
ALT 0–25 (%) ALT 26–40 (%)
Race (%)
White HBeAg+ 1 (9%) –Anti-HBe+ – 2 (13%)
Black HBeAg+ 1 (9%) 1 (5%)Anti-HBe+ 2 (22%) 2 (13%)
Asian HBeAg+ 9 (82%) 20 (95%)Anti-HBe+ 7 (78%) 11 (73%)
Hispanic HBeAg+ – –Anti-HBe+ – –
Sex (%)
Male HBeAg+ 2 (18%) 10 (48%)Anti-HBe+ 1(11%) 9 (56%)
a Viral loads not quantified above upper limits.b Some of the viral loads not quantified above upper limits.
766 M. Lai et al. / Journal of Hepatology 47 (2007) 760–767
Age is likely a surrogate marker of the duration ofdisease. The majority of our subjects were unable toreport how long they had chronic hepatitis B. Sincethe majority of our subjects were from Asia where verti-cal transmission or infection early in childhood waslikely, age was probably representative of duration inmost of these subjects. It is not surprising that age is a
Table 5
Predictors of significant fibrosis and inflammation-results of multiple
strong predictor of significant fibrosis in this chronic dis-ease in which damage develops over time. In fact, weconsider age above 40 to be a critical determinant inthe decision to biopsy and treat.
Given that active inflammation is the driving forceleading to fibrosis, it is also not surprising that increas-ing grade is associated with more fibrosis. In fact, onecould surmise that older age, more inflammation andactive viremia are all potential drivers of the fibroticprocess. Higher ALT, as a biomarker of inflammation,also predicts significant fibrosis, in HBeAg+ patients,but not in anti-HBe+ patients. This may be due to thedecreased power from the smaller sample afterstratification.
One of the shortcomings of our study was the inabilityto characterize the upper limit of viral replication in allsubjects. The PCR assays used in this study did not diluteserum to quantify the upper end and so the rangestopped at >200,000 copies/mL for many patients. Wecannot then comment on the absolute associationbetween viral load and fibrosis. Interestingly, HBeAg+may be an indicator of more active viral replicationand was associated with a minor increased risk of fibrosison biopsy. We only biopsied patients with HBV DNA>10,000 copies/mL and so cannot comment on patientswith even lower level HBV DNA replication. The corre-lation between HBV DNA and level of liver injury onbiopsy is not well characterized but there are some dataon the effect of HBV DNA reduction on improvement inliver injury. In an analysis of clinical trial data using oralnucleoside and nucleotide analogs, Mommeja-Marinshowed that there was a strong linear correlationbetween log reduction in HBV DNA and improvementin inflammation and fibrosis on liver biopsy [12]. Recentprospective follow-up studies of large cohorts of carriersfrom Asia found that high levels of HBV DNA wereindependent risk factors for the subsequent developmentof cirrhosis and HCC [1,7,10,13,14].
Are these findings of active inflammation and fibrosisin normal ALT patients really that surprising? We knowthat in hepatitis C infection, there are up to 25% ofpatients with persistently normal transaminase levelswho have been found to have significant fibrosis [15].In prior small preliminary studies, there have also beenreports of histological injury in patients with normalALT similar to the findings in this study [16,17]. We can-not exclude a referral bias in this study population butseveral factors suggest that this may be a typical sampleof U.S. HBV patients. First, biopsy was not selected butwas a standardized protocol for all patients with HBVDNA >10,000 copies/mL. Second, 90% of the referralbase of HBV patients is from affiliated Asian HealthCenters and although we cannot exclude that only thesicker population was being referred, the demographicsof the study populaton is highly representative of a typ-ical U.S. HBV cohort.
Table 6
Predictors of significant fibrosis and inflammation-results of multiple logistic regression analysis by HBeAg status
Odds ratio 95% CI p-Value
Predictors of significant fibrosis
Age (year) HBeAg+ 1.072 (1.013–1.136) 0.0170Anti-HBe+ 1.097 (1.017–1.184) 0.0165
Age (decade) HBeAg+ 2.012 (1.133–3.573) 0.0170Anti-HBe+ 2.528 (1.184–5.395) 0.0165
ALT Group HBeAg+ 1.767 (1.019–3.067) 0.0428EtOH Anti-HBe+ 30.724 (1.311–719.954) 0.0333
Predictors of significant inflammation
ALT HBeAg+ 1.885 (1.079–3.294) 0.0260Stage Anti-HBe+ 10.171 (1.830–56.526) 0.0080
M. Lai et al. / Journal of Hepatology 47 (2007) 760–767 767
Our findings strongly suggest that clinicians need toevaluate all patients with HBV DNA >10,000 copies/mL carefully for liver fibrosis and inflammation and thatage >40 years and an ALT above 25 may trigger evalu-ation with a liver biopsy. This population represents animportant number of patients with HBV at risk for dis-ease and further studies with non-invasive biomarkersfor liver injury and fibrosis should include this groupof patients.
References
[1] Oh KC, Park SH, Baek SH, Park CH, Hahn TH, Lee DK, et al.Idiopathic hypereosinophilic syndrome presenting as a single massin the liver. Korean J Gastroenterol 2004;43:61–65.
[2] Cecil RL, Goldman L, Bennett JC. Cecil textbook of medicine.21st ed. Philadelphia: W.B. Saunders; 2000, xli, 2308, clxx p.,[2318] p. of plates.
[3] Viral Hepatitis B. In: Center for Disease Control and Prevention;2003.
[4] Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carci-noma and decompensation in western European patients withcirrhosis type B. The EUROHEP Study Group on Hepatitis BVirus and Cirrhosis. Hepatology 1995;21:77–82.
[5] Liaw YF, Tai DI, Chu CM, Chen TJ. The development ofcirrhosis in patients with chronic type B hepatitis: a prospectivestudy. Hepatology 1988;8:493–496.
[6] Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after thedevelopment of cirrhosis in patients with chronic type B hepatitis:a prospective study. Liver 1989;9:235–241.
[7] Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predictingcirrhosis risk based on the level of circulating hepatitis B viralload. Gastroenterology 2006;130:678–686.
[8] Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, SchiffER, et al. A treatment algorithm for the management of chronichepatitis B virus infection in the United States: an update. ClinGastroenterol Hepatol 2006;4:936–962.
[9] Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology2007;45:507–539.
[10] Lin CL, Liao LY, Liu CJ, Yu MW, Chen PJ, Lai MY, et al.Hepatitis B viral factors in HBeAg-negative carriers with persis-tently normal serum alanine aminotransferase levels. Hepatology2007;45:1193–1198.
[11] Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D,Chazouilleres O, et al. Chronic hepatitis b virus carriers in theimmunotolerant phase of infection: histologic findings and out-come. Clin Gastroenterol Hepatol 2007;5:636–641.
[12] Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. SerumHBV DNA as a marker of efficacy during therapy for chronicHBV infection: analysis and review of the literature. Hepatology2003;37:1309–1319.
[13] Harris RA, Chen G, Lin WY, Shen FM, London WT, Evans AA.Spontaneous clearance of high-titer serum HBV DNA and risk ofhepatocellular carcinoma in a Chinese population. Cancer CausesControl 2003;14:995–1000.
[14] Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al.Hepatitis B e antigen and the risk of hepatocellular carcinoma. NEngl J Med 2002;347:168–174.
[15] Russo MW, Brown Jr RS. Should patients with chronic hepatitisC who have normal ALT levels be treated? Curr GastroenterolRep 2001;3:49–53.
[16] Wang C, Deubner H, Shuhart M, Manansala JN, Corey L,Kowdley KV. High prevalence of significant fibrosis in patientswith immunotolerance to chronic hepatitis B infection (abstr).Hepatology 2005;42:573A.
[17] Nguyen MH, Trinh H, Garcia RT, Ahmed A, Keeffe EB.Significant histologic disease in HBV-infected patients withnormal to minimally elevated ALT levels at initial evaluation(abstr). Hepatology 2005;42:593A.
