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213

Clinical Manifestations

Signs of HBV virus infection are exhibited by an incubation period from 45 to

120days (more extended periods have been described), with an average of 90days

in human beings. Symptoms and signs, when present, include fatigue, decreased

appetite, and jaundice and tend to appear 12weeks after exposure, when evidence

for infection and viral replication is fully exhibited by serology and laboratory nd-

ings of acute liver injury, e.g., high serum activity of ALTand aspartate aminotrans-

ferase (AST), which may persist for 12weeks [68].

Extrahepatic Manifestations

Polyarteritis nodosa (PAN)is a type of necrotizing vasculitis that affects middle size

arteries. It is reported to be associated with HBV infection in a third of the patients.

The pathogenesis of polyarteritis nodosa is considered to be from the deposition of

immune-complexes in association with HBsAg in the renal lesions. From a large

retrospective study in France that comprised 150 patients, it was documented that

seroconversion to e antibody was higher when antiviral therapy, which included

interferon and ribavirin, was added to cyclophosphamide and plasmapheresis. It

was also associated with complete remission, after which relapses were uncommon

after seroconversion. Antineutrophil cytoplasmic antibodies (ANCA) were not

detected in any of the patients. Renal disease was always associated with renal vas-

culitis, and glomerulonephritis was not [69].

Renal disease associated with HBV infection includes membranous nephropa-

thy, membranoproliferative glomerulonephritis (MPGN), and PAN (see above). The

pathogenesis of HBV-related kidney disease concerns the deposition of HBsAg-

antibody complexes in renal lesions and that of HBeAg in membranous nephropa-

thy. In addition, mesangial proliferative glomerulonephritis, immunoglobulin A

(IgA) nephropathy, crescentic glomerulonephritis, focal segmental glomeruloscle-

rosis (FSGS), and minimal change disease have been reported in association with

HBV infection [70].

Membranous nephropathy is characterized by the deposition of immune com-

plexes in the subepithelial region of the glomerular basement membrane. Proteinuria

and nephrotic syndrome are clinical manifestations, and in adults, microscopic

hematuria was common. In children, the condition tends to be self-limited and

resolves in association with seroconversion from e antigen to anti e antibody; in

adults, spontaneous resolution is not common, and the disease can progress to end

stage renal disease [71].

MPGN associated with HBV infection manifests itself with proteinuria, hematu-

ria, renal insufciency, and hypertension. In this condition, antigen-antibody com-

plexes are deposited in the mesangium and subendothelial space [70]. MPGN can

be associated with hepatitis B related mixed cryoglobulinemia [72]. In addition to

7 Chronic Hepatitis B

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214

the clinical presentation of MPGN, patients with cryoglobulinemia present with a

purpuric rash and low serum complement and rheumatoid factor in serum. The con-

dition can progress to end stage renal disease in spite of antiviral and immunosup-

pressive therapy [72].

Extrahepatic manifestations that include Guillain Barre syndrome [73], myopa-

thies [74], and hearing loss [75] have also been reported.

Characteristics ofChronic Hepatitis B Virus Infection

Certain serological, biochemical, and histological features that characterize chronic

hepatitis B have been labeled as phases, immune tolerant (or low inammatory

phase based on the ndings of specic T cell response to HVB [76]), immune

active, and inactive (Table7.1) [77, 78].

One of the features of chronic hepatitis B is the episodic increases in serum AST

and ALT activities sometimes accompanied by hyperbilirubinemia, known as ares,

which are described in Table7.2. The ares have been generally dened as an abrupt

increase in serum ALT activity to greater than ve times the upper limit of normal

[90] and associated with: (i) an increase in immune mediated inammatory activity

that includes an increase in HBcAg/HBeAg-specic precursor T cell frequencies

[96], (ii) increased production in interferon gamma [97], increased hepatic expres-

sion of IL-2 and IFN-gamma mRNA, mostly in the increased ALT activity phase,

with IL-4 mRNA in the decreased activity phase, ndings suggestive of augmented

liver inammatory response by Th-1 related cytokines, and decreased inammatory

response by Th-2 related cytokines [98], (iii) a decline in HBcAg-specic T(reg) in

association with an increase in HBcAg peptide-specic cytotoxic T lymphocyte

frequencies, features interpreted to suggest that the former cells mediate the immune

tolerant phase of the infection, and that their decline favors spontaneous ares [99],

(iv) an increase in IL-10-producing B cells [99], (v) an increase in TRAIL mediated

hepatocyte death by NK cells [27], high serum levels of CXCL-9 and CXCL-10

[100], and circulating and intra-hepatic programmed cell death (PD1) levels and

expression of its ligand PD-L1, nding interpreted to suggest that the local hepatic

PD-L1 may contribute to the persistence of the viral infection by creating an immu-

nosuppressive environment, thus inhibiting anti-HBV T cell expansion [101] that

could result in seroconversion from e antigen to anti e antibody status. The appear-

ance of increasing T cell responses to HBcAg/HBeAg usually occurs in the early

phase of acute exacerbations. These ndings imply that HBcAg/HBeAg-specic T

cells play an important role in exacerbating chronic hepatitis B and HBeAg sero-

conversion. HBcAg/HBeAg-specic precursor T cell frequencies were serially

studied in selected cases by limiting dilution assay. Elevation (two- to fourfold) of

HBcAg/HBeAg-specic precursor T cell frequencies contributed to increased

HBcAg/HBeAg-specic T cell proliferation during acute exacerbations (Table7.2).

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Table 7.1

Phases of hepatitis B virus infection [77, 78]

HBV DNA

(IU/ml)

ALT (IU/

ml)

antigen

in serum

Anti e

antibody

in serum Histology

Mode of

transmission/natural

history [

79]

Immune

tolerant

phase

200,000IU/

mL or

beyond

WNL Positive Negative Minimal or no

inammation or

brosis

• Usually

perinatallyacquired

• Long duration

(years)

• May be associated

with HCC at long

term

• May change to

immune active

phase (usually in

genotype C) [

80,

81]

Immune

active

phase

>20,000 Increased Positive Negative Inammation

with or without

brosis

• HBV DNA may

decrease

• Spontaneous

seroconversion, i.e.

loss of e Ag and

development of anti

e antibody

• Seroconversion

may be associated

with hepatitis are,

decreased rate of

decompensation

and increased

survival [79, 82, 83]

Immune

active

>2000 Increased Negative Positive Inammation

with or without

brosis

• Remains in

association with

activity

• Changes to

inactive phase and

exhibits episodes of

reactivation [

79, 83,

84]

Inactive

phase

<2000IU/

WNL Positive Minimal or

absent

inammation,

presence of

brosis that can

decrease over

years

• Histological

improvement

overtime

• HBV DNA

remains low or not

detectable [85–88]

HBV DNA hepatitis B deoxyribonucleic acid; ALT alanine aminotransferase; WNL within nor-

mal limits

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Table 7.2 Characteristics of chronic hepatitis B ares [89]

Proposed

precipitants/

proportion of

patients that

experience ares

Population/serology/

clinical manifestations/

serum transaminases

activity Immunology Serology Histology Outcomes

Spontaneous ares Change in

immune

recognition of

HBV/10–30%

per year

Mostly adults and

MSM, infection with

HIV, bacterial

infections, surgery/

pregnancy/

asymptomatic or

anorexia, fatigue,

nausea; liver failure

can occur especially in

advanced disease/2 to

5 times ULN

Expansion of T

cells reactive to

HBeAg and

HBcAg in early

phase with

subsequent

decrease if

seroconversion to

anti e Ab occurs

(1) Anti e Ab+

and negative

HBV DNA

(2) + HBeAg

and + HBV

DNA, or

− HBV DNA if

ongoing are

activity has

been followed

seroconversion

to anti e Ab

(3) In precore

mutant HBV

with + HBV

DNA but–

HBeAg IgM

anti-core can

reappear during

chronic hepatitis

B ares

CD8+ CTL

reactive to

hepatocyte

surface

associated

HBcAg

peptides/

hepatocellular

necrosis with

lobular hepatitis/

ares associated

with disease

progression

Seroconversion to anti e Ab in

50% of patients with serum

ALT >5 times ULN, and >60%

at 12–18months of follow-up

post are [

90]

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Proposed

precipitants/

proportion of

patients that

experience ares

Population/serology/

clinical manifestations/

serum transaminases

activity Immunology Serology Histology Outcomes

In association with

cytotoxic and

immunosuppressive

therapy

Increased

replication and

infection to a

large hepatocyte

population and

enhanced

recognition of

HBV by immune

system

Chemotherapy,

biological, and post

organ transplantation

recipients/14 to 72%

of subjects with

chronic or prior

exposure to HBV

infection/HB sAg+

(most common), + anti

core Ab alone and +

anti core and anti

HBs+/hepatitis with

and without

hyperbilirubinemia,

fulminant hepatitis

HBsAg+,

anti-core Ab+

and anti-HBs,

alone or in

combination.

Titers of all

tended to

decrease during

therapy

Lobular

hepatitis,

submassive

hepatic necrosis,

brosing

cholestatic

hepatitis (in post

OLT patients)

(1) For review [91]

(2) Mortality of 5.2% (vs 0.0%

in association with prophylaxis

with NA in patients on

chemotherapy for lymphoma

[92]

(3) 50% reactivation during

chemotherapy in hematological

malignancies, 20% after

chemotherapy; no deaths [93]

(4) In solid tumors, in

comparison with early

identication, late identication

of chronic HBV infection

associated with ares, HR,

4.02

; hepatic impairment,

HR=8.48

; liver failure=HR,

9.38

; death=HR, 3.90

[94]

(5) Hematological

malignancies, death was

increased by 7.8 times in

patients with late identication

of HVB

[94]

In association with

antiviral therapy with

interferon

Increased

immune

recognition

25% of subjects on

treatment

Decrease and ultimate

suppression of serum HBV

DNA and seroconversion to

anti e Ab

(continued)

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Proposed

precipitants/

proportion of

patients that

experience ares

Population/serology/

clinical manifestations/

serum transaminases

activity Immunology Serology Histology Outcomes

HBsAg+ in

association with

lamivudine

(nucleoside

analogue)

(1) Increased

immunological

recognition of

HBV in

association with

reduction of

viral replication

(2) Resurgence

of wild-type

HBV virus

(1) 10% of subjects on

treatment/AST and

ALT 3 times over

baseline

(2) Flare in association

with discontinuation of

treatment

In association with

HBV genotypic

variations:

(1) Pre-core mutants

(2) Basal core

promoter (BCP)

Absence of e Ag

production

possibly

associated with

decreased

immune

tolerance and

increased

immunologic

response to core

Ag on

hepatocyte

surface

(1) Common at the

time mutations appear

and decrease in

frequency when the

majority of the

infecting HVB is

comprised of the

pre-core mutant variant

(2) BCP

(2) Decrease in

e antigen

production and

increase in

HBV DNA

(2) Active

histology

Proposed

precipitants/

proportion of

patients that

experience ares

Population/serology/

clinical manifestations/

serum transaminases

activity

Immunology Serology Histology Outcomes

Table 7.2 (continued)

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Proposed

precipitants/

proportion of

patients that

experience ares

Population/serology/

clinical manifestations/

serum transaminases

activity Immunology Serology Histology Outcomes

In association with

infections with

hepatitis A, C, and D

Superimposed

liver injury; may

be severe and

fulminant

Patients with chronic

hepatitis B

Decrease in

serum HBV

DNA and loss

of e Ag possibly

from

interference to

viral replication

In association with

HIV

(1) Clearance of

serum HBV

DNA from

immune

reconstitution

from anti HIV

treatment

(2) Reactivation

of HVB due to

decrease in

serum HIV RNA

with subsequent

loss of cytokine

control on HBV

replication

(1) Loss of

HBV DNA in

association with

are

e anti + children

HR=hazard ratio, 95% condence interval [CI]

(1.26–12.86);

(1.86–38.66;

(1.50–58.86);

(1.19–12.83)

(1.73–35.27)

Fialuridine is a nucleoside analogue that was associated with marked decrease in HBV DNA but also with lactic acidosis and death. It is not in use and it will

not be discussed in this chapter [95]

ULN upper limit of normal; CTL cytotoxic T lymphocytes; NA nucleos(t)ide analogues

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220

Laboratory Findings andSerology

Following the incubation and prodrome, frank hepatitis with serum ALT activity

from several hundred to low thousands, mild to modest hyperbilirubinemia, hypoal-

buminemia, and sometimes short lasting coagulopathy; there can be leukopenia

with a predominance of lymphocytes. The hepatic panel, which most strikingly

exhibits high serum activity of ALT, normalizes itself over approximately 12weeks

from the initial documented abnormality. The liver prole of patients with chronic

hepatitis B varies in reference to the stage of the disease and it can be normal, or

with serum activity of transaminases several times the upper limit of normal.

In the context of viral hepatitis B markers, HBsAg can be detected in the serum

of acutely infected persons for a period of 1–9weeks, with an average of four, and

it is the only marker of hepatitis B detected after the initial infection; patients who

clear the infection do not have any measurable surface antigen by 15weeks, in gen-

eral, after the start of symptoms. HBV DNA at high concentrations, indicative of

viral replication, is detected in serum soon after the time of infection until 15weeks

after such, its absence coinciding with the disappearance of HBsAg. In fty percent

of patients who clear the acute infection, HBV DNA and HBsAg cannot be detected

in serum by week seven after initial clinical manifestations. HBe antigen, which

correlates with high HBV DNA levels and is a reection of high infectivity, is

detected in the serum from the time of infection until approximately 14weeks after,

followed by the rise of anti HBe antibody, which remains present as immunological

evidence of infection. Total and IgM anti-core antibodies rise to detectable levels

6weeks after infection; IgM anti-core antibody peaks at week 16 and decreases

gradually to undetectability by week 30 post infection, whereas IgG anti-core peaks

at week 20 and remains, usually for life, as evidence of prior infection. The window

period is characterized by the absence of HBsAg and anti HBs; at this time, the

presence of HBV infection can only be conrmed if anti-core antibodies are mea-

sured, highlighting the importance of the development of this assay [102] in medi-

cine and epidemiology [103, 104]. The case denition of chronic hepatitis B by the

CDC is the absenceof IgM anticore antibodiesand positive HBsAg, or HBeAg, or

hepatitis B virus DNA, including qualitative, quantitative, and genotype testing, or

HBsAg positive or HBV DNA positive, also including qualitative, quantitative, and

genotype testing or HBeAg positive in two occasions at least 6months apart [105].

High HBV DNA in serum and the presence of HBe antigen is characteristic of

patients who have entered the chronic phase of viral hepatitis B; the rate of serocon-

version, i.e., loss of e antigen and development of anti e antibody is 8–12% per year

in patients who develop chronic infection. Patients with chronic hepatitis B with and

without cirrhosis can develop hepatocellular carcinoma (HCC), as well as compli-

cations of chronic liver disease, including portal hypertension and its consequences,

and liver failure.

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Differential Diagnosis

Causes of acute or chronic hepatitis, including viral, autoimmune, metabolic, and

toxic (e.g., drug-induced), must be excluded in patients who present with increased

serum activity of transaminases, with or without hyperbilirubinemia.

Liver Histology

The histology of acute HBV infection is similar to that of other forms of acute hepa-

titis. It is noted that in acute hepatitis B, lymphocytes and macrophages are identi-

ed in contact with infected hepatocytes, consistent with the immune mediated

mechanism recognized to mediate HBV hepatitis. The mechanisms by which hepa-

tocellular death is mediated include rupture of ballooned hepatocytes and apoptosis,

the latter having been dened as the most relevant [106]. The feature that character-

izes HBV infected hepatocytes is the ground-glass hepatocyte, which can be identi-

ed by its expression of HBsAg by immunohistochemistry, or by the orcein or

Victoria blue stains. It is a feature of chronic infection as the identication of

HBsAg, as expressed by ground-glass hepatocytes, in acute and fulminant cases is

uncommon (Fig.7.1) [106]. Hepatitis B core antigen is found in the cytoplasm in

association with active inammatory activity [106]; it is also found in the nucleus,

where it is believed to represent empty nucleocapsids [107].

The histological diagnostic features of chronic HBV infection include marked

hepatocellular polymorphism and what has been described as dysplastic

Fig. 7.1 Liver histology

from a patient with chronic

hepatitis B and diffuse

surface antigen hepatocyte

expression as evidenced by

orcein stain (arrow) (40X)

7 Chronic Hepatitis B

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222

hepatocytes [108], characterized by enlargement of hyperbasophilic nuclei and

eosinophilic swelling of the cytoplasm of perivenular hepatocytes [107].

Inammatory changes in bile ducts and lymphoid follicles are not common; when

present, coinfection with HCV or HDV is suggested. Satellitosis, dened as single

hepatocytes surrounded by lymphocytes, can also be found. Flares tend to affect

zone III, i.e., pericentrally, and characterized by ballooning of hepatocytes.

Natural History ofChronic Hepatitis B

In patients with chronic hepatitis B, spontaneous losses of hepatitis B surface anti-

gen (HBsAg) occur in 0.2–0.8% per year [109]. This event, which has been termed

recovery phase, is associated with a decrease in brosis; however, HBV DNA can

be detected in serum at a reported frequency of 21% 5years after antigen loss. A

study on the HBsAg seroclearance in 92 Chinese patients with chronic hepatitis B

documented HBsAg loss at a mean age of 48.8years [110]. Seroconversion was

reported to be associated with a signicant decrease in serum ALT activity. Clearance

of HBsAg was documented more frequently in patients infected with genotype B

than in those infected with genotype C.Ninety-eight percent of the patients did not

have HBV DNA in serum, and 37% had HBV DNA in the liver, mostly in the form

of cccDNA.Liver histology was reported as almost normal in association with sero-

clearance of HBsAg; however, there was no difference in the risk of development of

HCC between patients with and without HBsAg seroclearance, although the age at

which seroclearance occurred was greater in patients with HCC [110]. These results

underscore the importance of screening for HCC in patients who have had chronic

hepatitis B.It also highlights the fact that the recovery phase is not always associ-

ated with the absence of complications from chronic HBV infection.

In regard to patients with chronic hepatitis B, e antigen negative, anti-e positive

serology there is a consensus that supports that a serum concentration of HBV DNA

greater than 2000 IU/ml (greater than 10

genomic copies/ml) can be associated

with liver injury; thus, it is the level at which a liver biopsy may be considered if

information on liver histology is required, e.g., prior to starting therapy in patients

with normal ALT and HBV DNA consistently documented as described above [77,

78]. It was documented that liver inammation and brosis were present in 90% of

subjects with HBV DNA greater than 20,000IU/ml and high serum ALT activity, in

10% of those with HBV DNA between 2000 and 20,000IU/ml, and in 1% of those

with serum HBV DNA less than 2000IU/ml [110]. A series of studies have docu-

mented a relationship between gender, age, HBV DNA, and the presence of cirrho-

sis with the development of HCC in patients with chronic HBV infection [111]. In

28,870 subjects from Taiwan with chronic hepatitis B with a median age of 46years

at study entry, 4155 of whom were HBsAg-positive and 3653 had a baseline HBV

DNA available, were followed for 11.4years. It was documented that subjects who

had an HBV DNA greater than 2000IU/ml at entry and at the end of the follow-up

period were at risk for the development of HCC.This information has contributed

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