clinical, biochemical, immunological and virological profiles of, and differential diagnosis...

8/10/2019 Clinical, Biochemical, Immunological and Virological Profiles of, And Differential Diagnosis Between, Patients With

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H E P A T O L O G Y

Clinical, biochemical, immunological and virological profiles

of, and differential diagnosis between, patients with acute

hepatitis B and chronic hepatitis B with acute flareYongnian Han, Qun Tang, Wei Zhu, Xiaoqing Zhang and Longying You

Research Unit of Liver Disease, Shanghai No. 8 Peoples Hospital, Shanghai, China

Abstract

Background and Aim: In areas with high or intermediate endemicity for chronic hepatitis

B virus (HBV) infection, it is difficult to distinguish acute hepatitis B (AHB) from chronic

hepatitis B with an acute flare (CHB-AF) in patients whose prior history of HBV infection

has been unknown. The present study aimed to screen laboratory parameters other than

immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc) to discriminate

between the two conditions.

Methods: A retrospective and prospective study was conducted in patients first presenting

clinically as HBV-related acute hepatitis to sort out acute self-limited hepatitis B (ASL-

HB). Then, clinical and laboratory profiles were compared between patients with ASL-HB

and CHB-AF. Parameters closely associated with ASL-HB were chosen to evaluate sensi-

tivity, specificity, accuracy, positive predictive values and negative predictive values for

diagnosing AHB.

Results: There were significant differences between patients with ASL-HB and CHB-AF

in relation to clinical and laboratory aspects, with many outstanding differences in levels of

serum HBV-DNA, hepatitis B e antigen (HBeAg) and alpha-fetoprotein (AFP) as well as

IgM anti-HBc. In particular, there was a greater difference between the two groups in low

levels of HBeAg (ratio of the optical density of the sample to the cut-off value [S/CO] 10upper reference

limit could rule out a probability of ASL-HB.

Key words

acute hepatitis B, alpha-fetoprotein, chronic

hepatitis B, differential diagnosis, hepatitis B

virus.

Accepted for publication 24 February 2008.

Correspondence

Dr Yongnian Han, Research Unit of Liver

Disease, Shanghai No. 8 Peoples Hospital,

8 Caobao Road, Shanghai 200235, China.

Email: [email protected]

Introduction

Hepatitis B virus (HBV) is a peculiar virus, leading to both an

acute infection and a chronic one. HBV-related acute hepatitis may

be a true episode of acute hepatitis B (AHB) or an acute flare of

chronic hepatitis B (CHB) hitherto unknown. It is important to

distinguish AHB patients, a great number of whom will have a

self-limited, benign course and not require intervention, from

patients with CHB with an acute flare (CHB-AF) who will

not have such a benign course and benefit from treatment with

antiviral agents.1

The presence of serum hepatitis B surface antigen (HBsAg)

with clinical and biochemical features of acute hepatitis usually

suggests AHB in patients from low HBV infection endemic areas

doi:10.1111/j.1440-1746.2008.05600.x

1728 Journal of Gastroenterology and Hepatology23 (2008) 17281733 2008 The Authors

Journal compilation 2008 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
mailto:[email protected]:[email protected]


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but not in patients from high or intermediate HBV endemic

regions, where AHB and CHB-AF may be misdiagnosed mutually,

especially if patients antecedent HBV carrier status is unknown.

Immunoglobulin M antibody to hepatitis B core antigen (IgM

anti-HBc) has been well recognized as a gold standard for

diagnosis of acute HBV infection.2,3 The commercially available

enzyme immunoassays (EIA) for IgM anti-HBc have been

designed to detect only higher titers of the antibody, but IgManti-HBc is present in approximately 1015% of patients with

CHB, especially in those with CHB-AF.2,3 IgM anti-HBc in high

titers had a high sensitivity (90100%) and specificity (90100%)

for the diagnosis of acute HBV infection.46 The results, however,

were obtained by comparison of acutely HBV-infected patients

with those with common CHB without an acute flare, even with

healthy individuals who were only positive for anti-HBc. When

CHB-AF was compared, IgM anti-HBc in a titer of 1:1000 had a

sensitivity of only 77.6% and a specificity of 70.0% for diagnosing

AHB.7 Although a fully automated microparticle chemilumines-

cent immunoassay in which significant specimen dilution and

multiple steps are avoided, has recently been developed, an ideal

cut-off value to differentiate AHB from CHB-AF seems not to be

established, because a great range (1.5, 2.42.5 and 10) of cut-offindex values have been reported in patients from Greece, Taiwan

and Italy; 9085% and 100%, respectively, regarding sensitivity

and 8690% and 99%, respectively, regarding specificity for diag-

nosing acute hepatitis B were shown in the two latter studies.810

However, the nearly perfect diagnostic power from Italys study

also resulted from comparison of AHB with common CHB

without acute exacerbation.10

Therefore, it is necessary to seek other parameters to assist IgM

anti-HBc to distinguish AHB from CHB-AF in patients with no

prior HBV infection history information whose diagnosis could

not be made by IgM anti-HBc alone during hospitalization. It has

been reported that HBV-DNA 10-fold the upper reference limit (URL), or total serum

bilirubin (TBil) >5 URL, and serum alkaline phosphatase (ALP)


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was less than 5, Fishers exact test was used for the data suitable

for a fourfold table and MannWhitneysU-test was used for those

unsuitable for a fourfold table. All tests were two-sided and all

analyses were carried out with the SPSS version 11.5 software

package (SPSS Inc., Chicago, IL, USA).

Sensitivity, specificity, accuracy, positive predictive values, and

negative predictive values of each or combinations of parameters

screened out were calculated, respectively.

Results

Outcomes of HBV-related acute hepatitis

Of the 219 patients with HBV-related acute hepatitis, 27 of 141

in the retrospective subgroup were not located, but none of 78 in

the follow-up subgroup was lost. Of 192 patients studied, 138 were

confirmed to have ASL-HB, diagnosed by the disappearance of

serum HBsAg, whereas the remaining 54 were shown to remain

HBsAg positive after remission of the disease, diagnosed as

having CHB, including CHB to which AHB evolved, and real

CHB with acute exacerbation that had not been found before,

which is a common phenomenon in China.

Clinical and biochemical characteristics

A comparison of clinical manifestations between 138 patients with

ASL-HB and 133 patients with an acute flare of known chronic

hepatitis B (CHB-AF group) is displayed in Table 1. No differ-

ences were found in sex, age and family history of CHB between

the two patient groups.

Symptomatic cases were more common (95.7% vs 79.7%,

P < 0.001) in the ASL-HB group than in the CHB-AF group.

Influenza-like symptoms including pyrexia, poor appetite and

vomiting were all observed in more patients with ASL-HB than in

those with CHB-AF. As for physical signs, jaundice was found

more frequently and splenomegaly more infrequently in ASL-HB

patients than in CHB-AF patients.

Compared to those with CHB-AF, ASL-HB patients had moresevere necroinflammation of the liver, being characterized by

higher levels of serum TBil, ALT, and GGT, but less impaired

instantaneous liver functions, being characterized by higher levels

of serum prealbumin, and a shorter PT (Table 2). One of the most

remarkable findings was a difference in serum AFP levels between

the two groups. Elevated levels of serum AFP were found in fewer

patients with ASL-HB than in those with CHB-AF (26.1% vs

63.2%,P < 0.001) and, among individuals with elevation of serum

AFP, ASL-HB patients had a far lower average concentration than

did patients with CHB-AF (13.9 ng/mL vs 171.7 ng/mL,

P < 0.001), with only one of 36 (2.8%) versus 42 of 85 (49.4%) in

the two groups, respectively, having an AFP level >5 URL

(35.1 ng/mL) (P < 0.001).

Immunological and virological characteristics

The prevalence of serum HBsAg and HBeAg was found to be

similar between the two groups, but the titers, as reflected by the

ratio of the optical density of the sample to the cut-off value

(S/CO) in the EIA method, were both lower, and the rate of HBeAg

seroconversion during hospitalization was higher in ASL-HB

patients than in those with CHB-AF (Table 3). An outstanding

finding was that HBeAg with S/CO


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more patients with ASL-HB than in those with CHB-AF (92.0%vs59.4%, P < 0.001), with a much greater difference between the

two groups existing in patients with a low level of HBeAg (S/CO


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sion for HBV in China.14,15 Thus, we have been taught that AHB is

rare in China after HBV infection has prevailed for centuries. The

lifetime risk of HBV infection, as judged by the peak prevalence ofHBV markers in elderly people, is approximately 80% in China,

but the rate of chronic HBV carriage is only 8.511.1%,14 suggest-

ing that a great majority of HBV-infected individuals have spon-

taneously cleared the HBV, particularly in adults. Taking this into

consideration, we paid special attention to the follow-up care of

adult patients with a first episode of HBV-related acute hepatitis

whose previous history of HBV infection had not been known.

During the follow-up period, most of them cleared HBV from their

serum and were confirmed as ASL-HB. Sequentially, we located

and retrospectively investigated the patients who were admitted

with signs, symptoms and biochemical tests suggestive of acute

hepatitis, and were diagnosed as CHB due to evidence of HBV

infection when they were discharged from our hospital fromJanuary 2003 to March 2005. A prospective arm on similar pati-

ents was conducted simultaneously. As we suspected, sporadic

ASL-HB is not rare but common now in China, opposite to what

has generally been accepted. So ensues a practical problem of

distinguishing AHB from CHB-AF. Here, we first compared

ASL-HB patients with CHB-AF patients in relation to clinical,

biochemical, immunological and virological aspects, and then

sought the methods to discriminate between the two diseases.

Comparison of patients with ASL-HB and CHB-AF had shown

that ASL-HB patients were more symptomatic, had a more severe

necroinflammatory liver but a more functionally compensated

liver. This finding could be explained by the fact that clinically

acute hepatitis occurred in a healthy and injured liver, respectively,

in the two conditions. Unfortunately, none of these biochemicalparameters at initial presentation could differentiate between

patients with ASL-HB and CHB-AF, which is in keeping with

Kumar et al.s observation.7

The cause of elevated AFP in patients with non-tumor liver

disease is unclear. Our findings that the peak production of a great

majority of the two groups of patients with elevated AFP levels

was observed at early phase of the disease, when liver damage was

the severest, but not at the convalescent phase (data not shown),

when hepatocytic regeneration occurred, suggest that elevations of

serum AFP in acute and chronic liver diseases may not be due to

subsequent hepatocyte regeneration induced by hepatic inflamma-

tion. The literature on the mechanism of serum AFP elevation in

AHB patients is not available at the present. Longitudinal studiesshowed that elevations of serum AFP levels at baseline in CHB

patients confirmed by liver biopsy had been proven to be associ-

ated with a higher risk of decompensated cirrhosis, hepatocellular

carcinoma (HCC),16,17 implying that patients with elevated serum

AFP had more advanced liver disease than did those with normal

levels. Very high levels of serum AFP suggestive of the possibility

of HCC were occasionally found in patients with chronic HBV

infection, especially those with cirrhosis, but no occurrence of

HCC.18,19 In the setting of chronic hepatitis C, the mean serum

AFP value was significantly greater in patients with more marked

fibrosis.20 All these observations put forward the hypothesis that

marked fibrosis or cirrhosis, a state of significant altered hepato-

cyte architecture, may be the underlying cause of increased serumAFP and, just at the presence of fibrosis or cirrhosis, hepatocyte

necroinflammation can trigger elevations of AFP. This can explain

why AFP elevations have frequently been found in CHB patients,

with remarkable AFP elevations being associated with exacer-

bations of the underlying liver disease,16,21 whereas normal AFP

levels are found in a great majority of patients with ASL-HB and

only low levels of AFP in a minority of them, although they had

more severe liver necroinflammation.

As shown by other researchers,7,10 ASL-HB patients had a

higher level of serum IgM anti-HBc, lower levels of serum HBV-

DNA, HBeAg and HBsAg than those with CHB-AF. These phe-

nomena can be explained by a rapid clearance of serum HBV-

DNA as a result of a coordinated response of innate and adaptive,

humoral and cellular immune systems in AHB.15,22 The reason whythe proportion of patients with negative HBeAg in the two groups

is similar (49.3%vs45.9%) is that some CHB patients are infected

with HBeAg-negative variants of HBV. The finding that a low level

of serum HBeAg was observed in more patients with ASL-HB

than in patients with CHB-AF suggests that a low HBeAg level is

more useful than negative HBeAg in the differential diagnosis

between ASL-HB and CHB-AF.

Very important differences in HBV-DNA, HBeAg and AFP, as

well as IgM anti-HBc, between the two groups have been observed

in our study. When used singly, the diagnostic power for ASL-HB

Table 4 Diagnostic performance of laboratory tests for ASL-HB

Laboratory tests Sensitivity Specificity Accuracy Positive

predictive

value

Negative

predictive

value

Positive IgM anti-HBc at 1:10 000 96.2 93.1 94.6 93.3 96.0

HBV-DNA


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of 1:10 000 IgM anti-HBc was comparable to what has been

reported,46 whereas that of HBV-DNA

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