0270-9139/87/0704-0758$02.
00/0
HEPATOLOCY
Copyright 0 1987 by the American Association for the Study of Liver Diseases
Special Articles
Chronic Type B Hepatitis and the “Healthy” HBsAg
Carrier State
JAYH. HOOFNAGLE,
DAVIDA.
Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, Maryland 20892; the Marion Bessin Liver Research Center, Albert Einstein College of Medicine,
Bronx, New York 10461; and the Stratton Laboratory for the Study of Liver Diseases, Mount Sinai School of Medicine of the City
University of New York, New York, New York 10029
Infection with the hepatitis B virus (HBV) can lead to
a variety of outcomes, acute type B hepatitis being only
the most clinically apparent and dramatic one. In fact,
prospective studies have shown that the majority of
persons (60 to 70%) infected with this virus do not
manifest an overt illness, but rather have a subclinical
infection producing antibody and seemingly permanent
immunity. For each case of clinically apparent acute type
B hepatitis, there are 2 or 3 cases of subclinical infection
(Figure 1) (1-3).
More important in the epidemiology and world-wide
significance of HBV, however, is the third possible out-
come of infection: development of the chronic HBsAg
carrier state. Between 5 to 10% of adults infected with
HBV develop a chronic infection manifested by the per-
sistence of HBsAg and virus in serum along with pro-
duction of viral antigens and HBV DNA in liver (1-3).
If infection occurs during childhood, this outcome is even
more frequent: indeed, HBV infection occurring during
the first few months of life almost invariably leads to
chronic infection (4,5). This chronic infection is usually
referred to as the “chronic HBsAg carrier state.”
What is the significance of the chronic carrier state in
regards to ultimate outcome, prognosis and infectivity?
Recent information provided by modern serological and
biochemical techniques have begun to clarify the features
of this chronic infection and its significance for man.
NOMENCLATURE
Some of the confusion regarding chronic HBV infec-
tion is actually due to confusion regarding nomenclature.
Patients who persist in having HBsAg in serum for 6 to
12 months are usually referred to as “chronic HBsAg
carriers.” However, chronic carriers vary enormously in
their clinical, serum biochemical, serologic and histologic
features (6-8). Some chronic HBsAg carriers have severe
and progressive liver disease; others are asymptomatic
and have minimal or no abnormalities of liver biochem-
ical tests. Some carriers are highly infectious and trans-
mit the infection to their close, personal contacts; other
carriers never seem to transmit the disease. Some chronic
HBsAg carriers have all of the HBV antigens and HBV
Address reprint requests to: Jay H. Hoofnagle, M.D., Liver Diseases
Section, Building 10, Room 4-D-52, National Institutes of Health,
Bethesda, Maryland 20892.
758
voi. 7, NO. 4,pp. 758-763.1987
Printed in U.5’.A.
SHAFRITZ AND HANSPOPPER
DNA detectable in both serum and liver; other carriers
have only HBsAg without detectable amounts of other
HBV antigens or even HBV DNA in serum or liver. How
can these various serological and clinical features of
patients with chronic HBV infection be resolved into a
unified concept of this chronic viral illness?
From a clinical viewpoint, chronic HBsAg carriers can
be divided into two forms: (i) those with chronic liver
disease and (ii) those without. The first group is usually
referred to as having “Chronic Type B Hepatitis” and
the second as having the “Asymptomatic, Healthy
Chronic HBsAg Carrier State.” Neither term is particu-
larly satisfactory, nor is either universally accepted.
More important than the lack of unanimity concerning
the actual terms, however, is the lack of unanimity
concerning their definition. The distinction between
these two forms of chronic HBV infection is often made
based upon the presence of clinical symptoms or the
presence of elevated serum aminotransferase activities.
Neither approach is always reliable. In this discussion,
we would like to provide new definitions which are based
not only on symptoms and aminotransferase activities
but also upon the state of virus replication.
CHRONIC TYPE B HEPATITIS VS. THE
“HEALTHY” CARRIER STATE
Clinical Symptoms. The presence or absence of
symptoms is often used to discriminate between HBsAg
carriers without significant liver disease (“asymptomatic
carriers”) and those with potentially serious forms of
chronic type B hepatitis. However, in chronic liver dis-
ease, clinical symptoms are an unreliable guide to the
presence or severity of chronic hepatic injury. While
“healthy” carriers are asymptomatic, so too are many
patients with chronic type B hepatitis. Indeed, the ma-
jority of patients with HBV-related chronic liver disease
have no symptoms or complain only of mild and inter-
mittent degrees of fatigue or lack of energy (6). Chronic
type B hepatitis is often a silent disease, and the absence
of symptoms does not accurately separate patients with
benign, self-limited illness from those with significant
progressive liver injury. In some instances, the initial
symptom of chronic type B hepatitis is actually the result
of a complication of an advanced cirrhosis (ascites or
variceal hemorrhage) that has taken years to develop.
Finally, “healthy” HBsAg carriers without liver disease
Vol. 7, No. 4, 1987 HBsAg CARRIER STATE
Death A Recovery
Transient
Subclinical
i Acute
Hepatitis B Virus
U Prospective studies of patients with chronic type B
Chronic Type B Hepatitis
Cirrhosis II “Healthy” HBs Ag Carrier
,, State
4 1 Hepatocellular Carcinoma
0”
Iroo
FIG.1. Outcomes of HBV infection in adults.
can have symptoms from unrelated illnesses which may
be incorrectly attributed to the chronic HBV infection.
Clinical symptoms should not be used to decide whether
an HBsAg-positive patient has chronic type B hepatitis
or is a “healthy” carrier.
Serum Biochemical Tests. Serum biochemical
tests results and in particular serum aminotransferase
activities are often used to decide whether the patient
with persistent HBsAg in serum has accompanying
chronic liver disease. Such biochemical laboratory tests
are much more reliable than clinical symptoms in defin-
ing which patients have hepatitis. However, the height
of the aminotransferase activities does not always accu-
rately reflect the severity of the liver disease, nor is it
clear what level of aminotransferase elevation should be
considered significant. Perhaps more importantly, the
cause of the aminotransferase elevations may not be the
chronic HBV infection, regardless of the presence of
HBsAg. This latter situation occurs with hepatitis delta
virus infections, which only occur in persons who are
HBsAg-positive and which can lead to severe chronic
liver disease (9, 10). Finally, some patients with chronic
type B hepatitis have periods when the serum amino-
transferase activities are normal or near normal, only to
be followed by periods when serum enzymes are markedly
elevated (6,ll-13). While serum aminotransferase activ-
ities are often used to distinguish between chronic type
B hepatitis and the “healthy” carrier state, they are not
always reliable.
Serological Tests. Analyses using modern serologic
and recombinant DNA techniques have suggested that
there are fundamental virologic differences between pa-
tients with chronic type B hepatitis and “healthy”
chronic HBsAg carriers. Patients with chronic liver dis-
759
ease due to HBV infection usually have detectable HBV
DNA and viral particles in serum and free or “replicative”
forms of HBV DNA in liver tissue. In contrast, “healthy”
carriers usually have no detectable HBV DNA in serum
and no free or “replicative” forms of viral DNA in liver
(6-8, 14-17). These patients may have small amounts of
HBV DNA in liver in integrated forms (i.e., high molec-
ular weight forms of viral DNA that have been incorpo-
rated into chromosomal DNA) (7, 8, 14, 18, 19). These
integrated forms of HBV DNA appear to synthesize
HBsAg but not other viral antigens nor intact virus.
Most studies also show that patients with chronic type
B hepatitis usually have HBeAg in serum, whereas
“healthy” carriers usually have anti-HBe (6, 18-24).
hepatitis suggest that these two forms of the carrier state
may actually represent just two different stages of per-
sistent HBV infection (5, 21, 24). As many as 30 to 50%
of patients with chronic type B hepatitis will sponta-
neously enter a sustained clinical remission of disease
with a fall in serum aminotransferase activities into the
normal range and disappearance of chronic inflamma-
tory liver disease activity. This change from chronic type
B hepatitis to the “healthy” carrier state is accompanied
by loss of HBeAg, HBV DNA and HBV-associated DNA
polymerase activity from the serum and seroconversion
to anti-HBe. Using recombinant DNA techniques, it has
been shown that patients undergoing such seroconver-
sion usually lose the “replicative” forms of HBV DNA
from the liver (25) and no longer circulate infectious
virus (26). Thus, the two different forms of chronic HBV
infection may actually represent two different phases in
the chronic viral infection: an early “replicative” and a
later “nonreplicative” phase (6, 8).
Several serologic tests have been proposed as sensitive
serum markers of active HBV replication. The test for
serum HBeAg is presently the most practical and gen-
erally available means of assessing the state of viral
activity. Most patients with active viral replication will
have HBeAg in serum; those without viral replication
usually have no HBeAg, but rather anti-HBe (6, 7).
Similarly, most patients with HBeAg will have chronic
type B hepatitis and most with anti-HBe are “healthy”
carriers. However, there are many exceptions. Not all
patients with HBeAg have raised serum aminotrans-
ferase activities, and in many, the degree of elevation is
mild. Certainly, the level of HBV replication as moni-
tored by HBeAg, DNA polymerase activity or HBV DNA
does not correlate with the severity of the chronic liver
disease (8, 24, 27). In fact, the reverse may be observed;
patients with low HBV levels in serum may have the
most severe and progressive forms of chronic liver disease
(28). Finally, many patients with severe HBsAg-positive
liver disease are HBeAg-negative and anti-HBe-positive,
especially in Mediterranean countries and Asia (8, 29).
Histologic Findings. Liver biopsy histology has
been the traditional standard by which to measure
whether a patient has significant underlying liver disease
or is a “healthy” carrier. The truly “healthy” carriers
should have normal or minimally abnormal liver histol-
ogy. The most common abnormality found among
“healthy” carriers is the ground-glass hepatocyte (Figure
760 HOOFNAGLE, SHAFRITZ AND POPPER HEPATOLOGY

2), a cell with abundant HBsAg in the cytoplasm that
can be stained nonspecifically by means of several stains,
most notably the Orcein, aldehyde-fuscin and Victoria
Blue stain (30, 31). “Healthy” carriers often have large
numbers of ground-glass cells, and indeed the findings
of these cells is pathognomic of the chronic carrier state,
as ground-glass hepatocytes rarely, if ever, are found
during acute type B hepatitis.
Thus, histologic features can be used to separate the
two categories of patients with chronic HBV infection:
chronic type B hepatitis and the “healthy” carrier state.
However, liver biopsy is not indicated routinely to follow
patients who are “healthy” carriers or who have no
evidence of progressive liver disease. Furthermore, liver
biopsy diagnosis is not invariably accurate in defining
these two categories of infection, because some forms of

FIG.2. The ground-glass hepatocyte of the chronic HBsAg carrier state. (a) H & E, 400X. (b) Victoria blue stain, 240X.
Vol. 7, No. 4, 1987 HBsAg CARRIER STATE 761

chronic type B hepatitis are mild and histologic lesions A patient with chronic type B hepatitis will typically
may be focal. Furthermore, sampling errors can occur have abnormal serum aminotransferase activities and
and the finding of minor abnormalities is no guarantee either HBeAg, HBV DNA and/or DNA polymerase ac-
that progressive liver disease and cirrhosis will not even- tivity in serum. Liver biopsy should reveal some degree
tually develop (32). The greatest limitation of routine of chronic hepatitis. The terms chronic persistent hepa-
liver histology, however, is that it does not provide infor- titis, chronic lobular hepatitis and chronic active hepa-
mation concerning the state of viral infection and repli- titis can be applied to the patient with chronic type B
cation. hepatitis, but they merely describe the severity and ex-
Useful in this regard are the use of newer techniques tent of the parenchymal and portal inflammatory process
that aid in defining the state of HBV infection. The most (38). Moreover, the severity of chronic type B hepatitis
easily applied technique is immunoperoxidase staining can change over time; a patient with chronic persistent
of liver for hepatitis B antigens (33-35). Reagents for hepatitis can later be found to have chronic active hep-
staining of HBsAg and HBcAg are now commercially atitis, and vice versa (6, 32).
available. Such techniques show that patients with
chronic type B hepatitis and active viral replication PROBLEMS IN DEFINING THE TWO FORMS OF
almost invariably have detectable HBcAg in liver (16, CHRONIC HBV INFECTION
27, 36); asymptomatic “healthy” carriers without evi-
dence of viral replication do not. In contrast, HBsAg can The preciseness of the proposed distinction between
be found in both situations and may actually be more chronic type B hepatitis and the “healthy” carrier state
prominent in “healthy” carriers (34). Other, more ele- is still somewhat deceptive. Some patients do not fall
gant, techniques for defining the state of HBV in liver easily into either category, and the differences between
include extraction and isolation of DNA (or RNA), fol- these two forms of infection may be more qualitative
lowed by molecular hybridization with radiolabeled than quantitative. These difficulties are especially prom-
cloned HBV DNA (7, 8, 14, 18, 19). Another method is inent if HBeAg is used as the only serologic marker for
in situ hybridization of liver tissue sections, using either active HBV replication.
radiolabeled or biotinylated HBV DNA (27, 37). These Many patients with significant HBsAg-positive liver
are currently difficult research techniques, but may be disease are negative for HBeAg and positive for anti-
the best standard for defining the state of HBV infection. HBe (8). Such patients may or may not have chronic
Combined Assessment. It is obvious that there is liver disease due to HBV. The disease can be said to be
no single, simple means of defining all aspects of chronic due to HBV infection if there is some evidence for active
HBV infection. An accurate assessment of whether a viral replication-either in the finding of DNA polymer-
patient has chronic type B hepatitis or is a “healthy” ase or HBV DNA in serum, or HBcAg or replicative
carrier requires analysis of a combination of clinical, forms of HBV DNA in liver. Unfortunately, these sero-
serum biochemical, serological and histological features logic markers may be present in low levels only or may
(Table 1). be present intermittently during bouts of hepatitis activ-
A “healthy” carrier then should be a person who has ity (6, 11). Alternately, HBsAg-positive patients with
had HBsAg in serum for at least 6 months, no symptoms anti-HBe in serum may have chronic liver disease from
of chronic liver disease, normal serum aminotransferase another cause such as superimposed delta hepatitis. In
activities and no detectable HBeAg, HBV DNA or DNA these cases, HBV replication is usually low or absent (9,
polymerase in serum. If liver biopsy tissue is available, it 10, 39).
should be normal or have minor, nonspecific focal ab- On the other hand, some patients with HBsAg and
normalities only, with HBsAg but not HBcAg, detectable HBeAg in serum have little or no detectable evidence for
in hepatocytes. chronic liver disease. This situation is particularly com-
mon in children, in hemodialysis patients and in immu-
TABLE1. Two forms of chronic HBV infection nosuppressed individuals (40-42). The lack of inflam-
Chronic type B “Healthy” carrier
matory liver disease in these patients is probably the
Feature
hepatitis state result of a deficient or absence immunologic response to
the active viral replication. Indeed, viral replication may
Symptoms Present or absent, Absent be “necessary” for chronic hepatitis B, but it is not
Signs Present, or absent Absent
“sufficient”: the virus itself does not seem to be cyto-
Aminotransferase ac- Elevated or normal Normal
tivities
pathic, instead, the hepatic injury in chronic hepatitis B
HBeAg Present or absent Absent appears to be due to an immunologic response to the
HBV DNA Present (sometimes Absent viral replication. The importance of the immune re-
intermit.tently) sponse in producing liver damage in this chronic viral
Liver biopsy Abnormal (some- Normal or minimal infection explains why the severity of disease does not
times minimally) nonspecific ab- correlate with the amount of virus present (27, 28) and
normalities correlates better with the level of antibody response to
HBsAg in liver Present or absent Usual present the virus (43). For this same reason, chronic HBsAg
HBcAg in liver Present Absent carriers with HBeAg but normal serum aminotransferase
HBV DNA in liver Episomal and Integrated or unde-
activities cannot be considered to be truly “healthy”
sometimes inte. tectable
grated as well HBsAg carriers, since chronic hepatitis may return upon
restoration of immune function (44-46).
 762 HOOFNAGLE, SHAFRITZ AND POPPER
These exceptions to the simple categorization of pa-
tients raise an important question. Are these virologic
differences between patients with chronic type B hepa-
titis and “healthy” HBsAg carriers qualitative or quan-
titative? Do “healthy” HBsAg carriers have absolutely
no HBV replication or is replication occurring focally ir,
rare hepatocytes, at a level that cannot be detected by
current techniques and to a degree that does not lead to
significant hepatitis?
The effects of integrated HBV DNA in the absence of
replicating virus has been recently investigated in “trans-
genic” mice (47, 48). Cloned fragments of HBV DNA
were inoculated into fertilized mouse oocytes and reim-
planted in pseudopregnant female mice. The resulting
“transgenic” offspring had integrated HBV DNA in cells,
and HBsAg in the serum that was produced in the liver,
and like “healthy” HBsAg carriers, had no serum bio-
chemical or histologic signs of liver disease. Thus, the
transgenic mouse may provide a dramatic model of what
may occur in the “healthy” carrier state-the persistence
of HBV DNA in these patients only in integrated and
“nonreplicative” forms. On the other hand, the occur-
rence of reactivation of chronic type B hepatitis with a
return of active viral replication in asymptomatic and
apparently “healthy” chronic HBsAg carriers suggests
that the differences between the two forms of chronic
HBV infection are actually quantitative, related to the
amount of viral replication that persists and the numbers
of hepatocytes in which this occurs (11-13,43,44).
Why are these distinctions, which depend on so many
factors and have so many exceptions, important? They
are important because these different forms of chronic
HBV infection may have different clinical implications.
The major complications and long-term adverse effects
of this chronic viral infection (Table 2) have been asso-
. ciated primarily with chronic type B hepatitis and have
” been less of a problem for the “healthy” carrier without
liver disease. Thus, “healthy” HBsAg carriers rarely
transmit infection to others (49) and usually do not have
progressive liver disease (32, 50). The immune complex
disorders associated with HBV infection are generally
found only in patients with active viral replication, and
loss of HBeAg and serum HBV DNA in these patients
is usually followed by a remission in the immune complex
disease (51, 52). Finally, a highly controversial question
is whether “healthy” HBsAg carriers are at a lower risk
TABLE2. Complications of chronic HBV infection
Infectiousness to contacts
Symptoms of chronic hepatitis
Immune complex disorders
Glomerulonephritis
Polyarteritis nodosa
Cryoglobulinemia
Raynaud‘s phenomenon
Arthralgias
Mucocutaneous vasculitis
Cirrhosis
Portal hypertension
Hepatocellular failure
Hepatocellular carcinoma
HEPATOLOGY
for development of primary hepatocellular carcinoma
compared to patients with chronic type B hepatitis (53).
The relationship between activity of chronic HBV infec-
tion and the development of hepatocellular carcinoma
will be discussed further in a companion article (54).
CONCLUSIONS
Features of the state of viral replication and activity
of liver disease need to be considered in dealing with
patients with chronic HBV infection. Chronic type B
hepatitis is not a static disease, and its activity and the
underlying state of HBV replication can change over
time. The separation and definition of patients as either
having chronic type B hepatitis or the “healthy” carrier
state can help in assessing the clinical importance of the
chronic viral infection. Recent advances in prevention
and treatment of type B hepatitis make these consider-
ations even more important. Ultimately, long-term fol-
low-up studies of a wide spectrum of HBsAg-positive
patients are needed to assess the long-term significance
of these two forms of chronic HBV infection.
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