2568 PART 10 Disorders of the Gastrointestinal System

whereas others are more geographically confined (see “Epidemiology

and Global Features”). In addition, differences exist among genotypes

in responsiveness to antiviral therapy but not in pathogenicity or clinical progression (except for genotype 3, in which hepatic steatosis and

clinical progression are more likely).

Currently available, third-generation immunoassays, which incorporate proteins from the core, NS3, and NS5 regions, detect anti-HCV

antibodies during acute infection. The most sensitive indicator of

HCV infection is the presence of HCV RNA, which requires molecular amplification by PCR or transcription-mediated amplification

(TMA) (Fig. 339-7). To allow standardization of the quantification of

HCV RNA among laboratories and commercial assays, HCV RNA is

reported as international units (IUs) per milliliter; quantitative assays

with a broad dynamic range are available that allow detection of HCV

RNA with a sensitivity as low as 5 IU/mL. HCV RNA can be detected

within a few days of exposure to HCV—well before the appearance of

anti-HCV—and tends to persist for the duration of HCV infection.

Application of sensitive molecular probes for HCV RNA has revealed

the presence of replicative HCV in peripheral blood lymphocytes of

infected persons; however, as is the case for HBV in lymphocytes, the

clinical relevance of HCV lymphocyte infection is not known.

Hepatitis E Previously labeled epidemic or enterically transmitted

non-A, non-B hepatitis, HEV is an enterically transmitted virus that

causes clinically apparent hepatitis primarily in India, Asia, Africa, and

Central America; in those geographic areas, HEV is the most common

cause of acute hepatitis; one-third of the global population appears to

have been infected. This agent, with epidemiologic features resembling

those of hepatitis A, is a 27- to 34-nm, nonenveloped, heat-stable,

HAV-like virus with a 7200-nucleotide, single-strand, positive-sense

RNA genome. Like HAV, HEV also exists in a quasi-enveloped form

enclosed within host-cell-derived membranes. HEV has three overlapping ORFs (genes), the largest of which, ORF1, encodes nonstructural proteins involved in virus replication (the viral replicase, which

includes a protease, polymerase, and helicase). A middle-sized gene,

ORF2, encodes the nucleocapsid protein, the major structural protein,

and the smallest, ORF3, encodes a small structural phosphoprotein

involved in virus particle secretion. All HEV isolates appear to belong

to a single serotype, despite genomic heterogeneity of up to 25% and

the existence of four species (A–D) and eight genotypes, only four of

which, all within species A, have been detected in humans; genotypes

1 and 2 (common in developing countries) appear to be more virulent

anthrotropic variants, whereas genotypes 3 (the most common in the

United States and Europe) and 4 (seen in China), endemic in animal

species (enzootic variants), are more attenuated, account for subclinical

infections, represent a zoonotic reservoir for human infections, and

can cause chronic infection in immunocompromised hosts. Contributing to the perpetuation of this virus are the animal reservoirs described

above, most notably in swine but also in camels, deer, rats, and rabbits,

among others. No genomic or antigenic homology, however, exists

between HEV and HAV or other picornaviruses; and HEV, although

resembling caliciviruses, is sufficiently distinct from any known agent

to merit its own classification as a unique genus, Orthohepevirus,

within the family Hepeviridae (which includes similar viruses infecting

mammals, birds, and fish). The virus has been detected in stool, bile,

and liver and is excreted in the stool during the late incubation period.

Both IgM anti-HEV during early acute infection and IgG anti-HEV

predominating after the first 3 months can be detected. The presence

of HEV RNA in serum and stool accompanies acute infection; viremia

resolves as clinical-biochemical recovery ensues, while HEV RNA

in stool may outlast viremia by several weeks. Currently, serologic/

virologic testing for HEV infection—not approved or licensed by the

U.S. Food and Drug Administration (FDA)—can be done in specialized laboratories (e.g., the Centers for Disease Control and Prevention

[CDC]) and some commercial laboratories.

■ PATHOGENESIS

Under ordinary circumstances, none of the hepatitis viruses is known

to be directly cytopathic to hepatocytes. Evidence suggests that the

clinical manifestations and outcomes after acute liver injury associated

with viral hepatitis are determined by the immunologic responses of

the host. Among the viral hepatitides, the immunopathogenesis of

hepatitis B and C has been studied most extensively.

Hepatitis B For HBV, the existence of inactive hepatitis B carriers

with normal liver histology and function suggests that the virus is

not directly cytopathic. The fact that patients with defects in cellular

immune competence are more likely to remain chronically infected

rather than to clear HBV supports the role of cellular immune

responses in the pathogenesis of hepatitis B–related liver injury. The

model that has the most experimental support involves cytolytic T cells

sensitized specifically to recognize host and hepatitis B viral antigens

on the liver cell surface. Nucleocapsid proteins (HBcAg and possibly

HBeAg), present on the cell membrane in minute quantities, are the

viral target antigens that, with host antigens, invite cytolytic T cells to

destroy HBV-infected hepatocytes. Differences in the robustness and

broad polyclonality of CD8+ cytolytic T-cell responsiveness; in the

level of HBV-specific helper CD4+ T cells; in attenuation, depletion,

and exhaustion of virus-specific T cells; in viral T-cell epitope escape

mutations that allow the virus to evade T-cell containment; and in

the elaboration of antiviral cytokines by T cells have been invoked to

explain differences in outcomes between those who recover after acute

hepatitis and those who progress to chronic hepatitis or between those

with mild and those with severe (fulminant) acute HBV infection.

Although a robust cytolytic T-cell response occurs and eliminates

virus-infected liver cells during acute hepatitis B, >90% of HBV DNA

has been found in experimentally infected chimpanzees to disappear

from the liver and blood before maximal T-cell infiltration of the

liver and before most of the biochemical and histologic evidence of

liver injury. This observation suggests that components of the innate

immune system and inflammatory cytokines, independent of cytopathic antiviral mechanisms, participate in the early immune response

to HBV infection; this effect has been shown to represent elimination

of HBV replicative intermediates from the cytoplasm and covalently

closed circular viral DNA from the nucleus of infected hepatocytes. In

turn, the innate immune response to HBV infection is mediated largely

by natural killer (NK) cell cytotoxicity, activated by immunosuppressive cytokines (e.g., interleukin [IL] 10 and transforming growth factor

[TGF] β), reduced signals from inhibitory receptor expression (e.g.,

major histocompatibility complex), or increased signals from activating receptor expression on infected hepatocytes. In addition, NK

cells reduce helper CD4+ cells, which results in reduced CD8+ cells

and exhaustion of the virus-specific T-cell response to HBV infection.

Adding to the evidence supporting the role of these immunologic

perturbations in the pathogenesis of HBV-associated liver injury are

the observations that many of these departures from normal immune

function are restored after successful antiviral therapy. Ultimately,

HBV-HLA–specific cytolytic T-cell responses of the adaptive immune

system are felt to be responsible for recovery from HBV infection.

Debate continues over the relative importance of viral and host factors in the pathogenesis of HBV-associated liver injury and its outcome.

0 1 2345 6 12 24 4 36 8 60 120

Anti-HCV

HCV RNA

ALT

Months after exposure

FIGURE 339-7 Scheme of typical laboratory features during acute hepatitis C

progressing to chronicity. Hepatitis C virus (HCV) RNA is the first detectable

event, preceding alanine aminotransferase (ALT) elevation and the appearance of

anti-HCV.

2569Acute Viral Hepatitis CHAPTER 339

As noted above, precore genetic mutants of HBV have been associated

with the more severe outcomes of HBV infection (severe chronic and

fulminant hepatitis), suggesting that, under certain circumstances,

relative pathogenicity is a property of the virus, not the host. The facts

that concomitant HDV and HBV infections are associated with more

severe liver injury than HBV infection alone and that cells transfected

in vitro with the gene for HDV antigen express HDV antigen and then

become necrotic in the absence of any immunologic influences are also

consistent with a viral effect on pathogenicity. Similarly, in patients

who undergo liver transplantation for end-stage chronic hepatitis B,

occasionally, rapidly progressive liver injury appears in the new liver.

This clinical pattern is associated with an unusual histologic pattern

in the new liver, fibrosing cholestatic hepatitis, which, ultrastructurally,

appears to represent a choking of the cell with overwhelming quantities of HBsAg. This observation suggests that, under the influence of

the potent immunosuppressive agents required to prevent allograft

rejection, HBV may have a direct cytopathic effect on liver cells, independent of the immune system.

Although the precise mechanism of liver injury in HBV infection

remains elusive, studies of nucleocapsid proteins have shed light on

the profound immunologic tolerance to HBV of babies born to mothers with highly replicative (HBeAg-positive), chronic HBV infection.

In HBeAg-expressing transgenic mice, in utero exposure to HBeAg,

which is sufficiently small to traverse the placenta, induces T-cell tolerance to both nucleocapsid proteins. This, in turn, may explain why,

when infection occurs so early in life, immunologic clearance does not

occur, and protracted, lifelong infection ensues. An alternative explanation proposed to explain why robust liver injury does not accompany

neonatal HBV infection but predisposes to chronic infection is defective priming of HBV-specific T cells during in utero exposure to HBV.

“IMMUNOTOLERANT” VERSUS “IMMUNOREACTIVE” CHRONIC

HEPATITIS B An important distinction should be drawn between

HBV infection acquired at birth, common in endemic areas, such as

East Asia, and infection acquired in adulthood, common in the West.

Infection in the neonatal period is associated with the acquisition of

what appears to be a high level of immunologic tolerance to HBV and

absence of an acute hepatitis illness but the almost invariable establishment of chronic, often lifelong infection. Neonatally acquired HBV

infection can culminate decades later in cirrhosis and hepatocellular

carcinoma (see “Complications and Sequelae”). In contrast, when HBV

infection is acquired during adolescence or early adulthood, the host

immune response to HBV-infected hepatocytes tends to be robust,

an acute hepatitis-like illness is the rule, and failure to recover is the

exception. After adulthood-acquired infection, chronicity is uncommon, and the risk of hepatocellular carcinoma is very low. Based on

these observations, some authorities categorize HBV infection into an

“immunotolerant” phase, an “immunoreactive” phase, and an “inactive” phase. This somewhat simplistic formulation does not apply at

all to the typical adult in the West with self-limited acute hepatitis B,

in whom no period of immunologic tolerance occurs. Even among

those with neonatally acquired HBV infection, in whom immunologic

tolerance appears to be established definitively, immunologic responses

to HBV infection have been demonstrated (albeit typically at reduced

levels), and intermittent bursts of hepatic necroinflammatory activity

punctuate the early decades of life during which liver injury appears

to be quiescent (labeled by some as the “immunotolerant” phase;

however, it more accurately is a period of dissociation between highlevel HBV replication and a paucity of inflammatory liver injury). In

addition, even when clinically apparent liver injury and progressive

fibrosis emerge during later decades (the so-called immunoreactive,

or immunointolerant, phase), the level of immunologic tolerance to

HBV remains substantial. More accurately, in patients with neonatally

acquired HBV infection, a dynamic equilibrium exists between tolerance and intolerance, the outcome of which determines the clinical

expression of chronic infection. Persons infected as neonates tend to

have a relatively higher level of immunologic tolerance (high replication, low necroinflammatory activity) during the early decades of life

and a relatively lower level (but only rarely a loss) of tolerance (and

necroinflammatory activity reflecting the level of virus replication) in

the later decades of life.

Hepatitis C Cell-mediated immune responses and elaboration

by T cells of antiviral cytokines contribute to the multicellular innate

and adaptive immune responses involved in the containment of infection and pathogenesis of liver injury associated with hepatitis C. The

fact that HCV is so efficient in evading these immune mechanisms

is a testament to its highly evolved ability to disrupt host immune

responses at multiple levels. After exposure to HCV, the host cell

identifies viral product motifs (pattern recognition receptors) that distinguish the virus from “self,” resulting in the elaboration of interferons

and other cytokines that result in activation of innate and adaptive

immune responses. Intrahepatic human leukocyte antigen (HLA) class

1–restricted cytolytic T cells directed at nucleocapsid, envelope,

and nonstructural viral protein antigens have been demonstrated in

patients with chronic hepatitis C; however, such virus-specific cytolytic

T-cell responses do not correlate adequately with the degree of liver

injury or with recovery. Yet a consensus has emerged supporting a role

in the pathogenesis of HCV-associated liver injury of virus-activated

CD4+ helper T cells that stimulate, via the cytokines they elaborate,

HCV-specific CD8+ cytotoxic T cells. These responses appear to be

more robust (higher in number, more diverse in viral antigen specificity, more functionally effective, and longer lasting) in those who

recover from HCV infection than in those who have chronic infection.

Contributing to chronic infection are a CD4+ proliferative defect that

results in rapid contraction of CD4+ responses, mutations in CD8+

T cell–targeted viral epitopes that allow HCV to escape immunemediated clearance, and upregulation of inhibitory receptors on functionally impaired, exhausted T cells. Although attention has focused on

adaptive immunity, HCV proteins have been shown to interfere with

innate immunity by resulting in blocking of type 1 interferon responses

and inhibition of interferon signaling and effector molecules in the

interferon signaling cascade.

Several HLA alleles have been linked with self-limited hepatitis

C, the most convincing of which is the CC haplotype of the IL28B

gene, which codes for interferon λ3, a component of innate immune

antiviral defense. The IL28B association is even stronger when combined with HLA class II DQB1*

03:01. The link between non-CC IL28B

polymorphisms and failure to clear HCV infection has been explained

by a chromosome 19q13.13 frameshift variant upstream of IL28B,

the ΔG polymorphism of which creates an ORF in a novel interferon

gene (IFN-λ4) associated with impaired HCV clearance. Also shown

to contribute to limiting HCV infection are NK cells of the innate

immune system that function when HLA class I molecules required

for successful adaptive immunity are underexpressed. Both peripheral

cytotoxicity and intrahepatic NK cell cytotoxicity are dysfunctional in

persistent HCV infection. Adding to the complexity of the immune

response, HCV core, NS4B, and NS5B have been shown to suppress

the immunoregulatory nuclear factor (NF)-κB pathway, resulting in

reduced antiapoptotic proteins and a resultant increased vulnerability

to tumor necrosis factor (TNF) α–mediated cell death. Patients with

hepatitis C and unfavorable (non-CC, associated with reduced HCV

clearance) IL28B alleles have been shown to have depressed NK cell/

innate immune function. Of note, the emergence of substantial viral

quasispecies diversity and HCV sequence variation allow the virus to

evade attempts by the host to contain HCV infection by both humoral

and cellular immunity.

Finally, cross-reactivity between viral antigens (HCV NS3 and

NS5A) and host autoantigens (cytochrome P450 2D6) has been

invoked to explain the association between hepatitis C and a subset

of patients with autoimmune hepatitis and antibodies to liver-kidney

microsomal (LKM) antigen (anti-LKM) (Chap. 341).

Hepatitis A and E Viral shedding in these acute hepatitides predates clinical evidence of liver injury, consistent with the absence of a

relationship between viral replication and target-organ injury. Instead,

as shown for hepatitis B and C, in hepatitis A and E, experimental

evidence supports a cytolytic CD8+ T-cell response as the instrument

2570 PART 10 Disorders of the Gastrointestinal System

of liver cell injury, in concert with or dwarfed by CD4+ helper T cells

or CD4+ interferon γ–secreting cells. HEV has also been shown to

interfere with host antiviral defenses, such as interferon signaling and

effector function, and to downregulate interferon-stimulated genes.

The demonstration of an activated innate immune response in patients

with these hepatitides argues for a multitude of immunologic mechanisms in the pathogenesis of the acute liver injury resulting from HAV

and HEV infection.

■ EXTRAHEPATIC MANIFESTATIONS

Immune complex–mediated tissue damage appears to play a pathogenetic role in the extrahepatic manifestations of acute hepatitis B.

The occasional prodromal serum sickness–like syndrome observed

in acute hepatitis B appears to be related to the deposition in tissue

blood vessel walls of HBsAg–anti-HBs circulating immune complexes,

leading to activation of the complement system and depressed serum

complement levels.

In patients with chronic hepatitis B, other types of immune-complex

disease may be seen. Glomerulonephritis with the nephrotic syndrome

is observed occasionally; HBsAg, immunoglobulin, and C3 deposition

has been found in the glomerular basement membrane. Whereas

generalized vasculitis (polyarteritis nodosa) develops in considerably

<1% of patients with chronic HBV infection, 20–30% of patients

with polyarteritis nodosa have HBsAg in serum (Chap. 363). In

these patients, the affected small- and medium-size arterioles contain

HBsAg, immunoglobulins, and complement components. Another

extrahepatic manifestation of viral hepatitis, essential mixed cryoglobulinemia (EMC), was reported initially to be associated with hepatitis B.

The disorder is characterized clinically by arthritis, cutaneous vasculitis (palpable purpura), and, occasionally, glomerulonephritis and

serologically by the presence of circulating cryoprecipitable immune

complexes of more than one immunoglobulin class (Chaps. 314 and

363). Many patients with this syndrome have chronic liver disease, but

the association with HBV infection is limited; instead, a substantial

proportion has chronic HCV infection, with circulating immune complexes containing HCV RNA. Immune-complex glomerulonephritis

is another recognized extrahepatic manifestation of chronic hepatitis

C (see “Complications and Sequelae,” below). Immune-complex disorders have been linked, albeit rarely, with both hepatitis A and E.

In hepatitis E, rare neurologic (including Guillain-Barré syndrome),

renal, pancreatic, and hematologic complications have been postulated

to result from both immunologic mechanisms and/or direct extrahepatic-site infection with the virus.

■ PATHOLOGY

The typical morphologic lesions of all types of viral hepatitis are

similar and consist of panlobular infiltration with mononuclear cells,

hepatic cell necrosis, hyperplasia of Kupffer cells, and variable degrees

of cholestasis. Hepatic cell regeneration is present, as evidenced by

numerous mitotic figures, multinucleated cells, and “rosette” or “pseudoacinar” formation. The mononuclear infiltration consists primarily

of small lymphocytes, although plasma cells and eosinophils occasionally are present. Liver cell damage consists of hepatic cell degeneration

and necrosis, cell dropout, ballooning of cells, and acidophilic degeneration of hepatocytes (forming so-called Councilman or apoptotic

bodies). Large hepatocytes with a ground-glass appearance of the cytoplasm may be seen in chronic but not in acute HBV infection; these

cells contain HBsAg and can be identified histochemically with orcein

or aldehyde fuchsin. In uncomplicated viral hepatitis, the reticulin

framework is preserved.

In hepatitis C, the histologic lesion is often remarkable for a relative

paucity of inflammation, a marked increase in activation of sinusoidal

lining cells, lymphoid aggregates, the presence of fat (more frequent

in genotype 3 and linked to increased fibrosis), and, occasionally, bile

duct lesions in which biliary epithelial cells appear to be piled up without interruption of the basement membrane. Occasionally, microvesicular steatosis occurs in hepatitis D. In hepatitis E, a common histologic

feature is marked cholestasis. A cholestatic variant of slowly resolving

acute hepatitis A also has been described.

A more severe histologic lesion, bridging hepatic necrosis, also

termed subacute or confluent necrosis or interface hepatitis, is observed

occasionally in acute hepatitis. “Bridging” between lobules results

from large areas of hepatic cell dropout, with collapse of the reticulin framework. Characteristically, the bridge consists of condensed

reticulum, inflammatory debris, and degenerating liver cells that span

adjacent portal areas, portal to central veins, or central vein to central

vein. This lesion had been thought to have prognostic significance; in

many of the originally described patients with this lesion, a subacute

course terminated in death within several weeks to months, or severe

chronic hepatitis and cirrhosis developed; however, the association

between bridging necrosis and a poor prognosis in patients with acute

hepatitis has not been upheld. Therefore, although demonstration of

this lesion in patients with chronic hepatitis has prognostic significance

(Chap. 341), its demonstration during acute hepatitis is less meaningful, and liver biopsies to identify this lesion are no longer undertaken

routinely in patients with acute hepatitis. In massive hepatic necrosis

(fulminant hepatitis, “acute yellow atrophy”), the striking feature at

postmortem examination is the finding of a small, shrunken, soft liver.

Histologic examination reveals massive necrosis and dropout of liver

cells of most lobules with extensive collapse and condensation of the

reticulin framework. When histologic documentation is required in

the management of fulminant or very severe hepatitis, a biopsy can be

done by the angiographically guided transjugular route, which permits

the performance of this invasive procedure in the presence of severe

coagulopathy.

Immunohistochemical and electron-microscopic studies have localized HBsAg to the cytoplasm and plasma membrane of infected liver

cells. In contrast, HBcAg predominates in the nucleus, but, occasionally, scant amounts are also seen in the cytoplasm and on the cell membrane. HDV antigen is localized to the hepatocyte nucleus, whereas

HAV and HCV antigens are localized to the cytoplasm. Hepatitis E

ORF-2 protein staining is distributed in both a cytoplasmic and nuclear

pattern.

■ EPIDEMIOLOGY AND GLOBAL FEATURES

Before the availability of serologic tests for hepatitis viruses, all viral

hepatitis cases were labeled either as “infectious” or “serum” hepatitis.

Modes of transmission overlap, however, and a clear distinction among

the different types of viral hepatitis cannot be made solely based on clinical or epidemiologic features (Table 339-2). The most accurate means

to distinguish the various types of viral hepatitis involves specific

serologic testing.

Hepatitis A This agent is transmitted almost exclusively by the

fecal-oral route. Person-to-person spread of HAV is enhanced by poor

personal hygiene and overcrowding; large outbreaks as well as sporadic cases have been traced to contaminated food, water, milk, frozen

raspberries and strawberries, green onions imported from Mexico, and

shellfish (e.g., scallops imported from the Philippines used to make

sushi, the culprit identified in a 2016 Hawaiian outbreak). Intrafamily

and intrainstitutional spreads are also common. Early epidemiologic

observations supported a predilection for hepatitis A to occur in late

fall and early winter. In temperate zones, epidemic waves have been

recorded every 5–20 years as new segments of nonimmune population

appeared; however, in developed countries, the incidence of hepatitis

A has been declining, presumably as a function of improved sanitation,

and these cyclic patterns are no longer observed. No HAV carrier state

has been identified after acute hepatitis A; perpetuation of the virus in

nature depends presumably on nonepidemic, inapparent subclinical

infection, ingestion of contaminated food or water in, or imported

from, endemic areas, and/or contamination linked to environmental

reservoirs.

In the general population, anti-HAV, a marker for previous HAV

infection, increases in prevalence as a function of increasing age and

of decreasing socioeconomic status. In the 1970s, serologic evidence of

prior hepatitis A infection occurred in ~40% of urban populations in

the United States, most of whose members never recalled having had

a symptomatic case of hepatitis. In subsequent decades, however, the

2571Acute Viral Hepatitis CHAPTER 339

prevalence of anti-HAV declined in the United States. In developing

countries, exposure, infection, and subsequent immunity are almost

universal in childhood. As the frequency of subclinical childhood

infections declines in developed countries, a susceptible cohort of

adults emerges. Hepatitis A tends to be more symptomatic in adults;

therefore, paradoxically, as the frequency of HAV infection declines,

the likelihood of clinically apparent, even severe, HAV illnesses

increases in the susceptible adult population. Travel to endemic areas

is a common source of infection for adults from nonendemic areas.

Important recognized epidemiologic foci of HAV infection include

childcare centers, neonatal intensive care units, promiscuous men

who have sex with men, injection drug users, and unvaccinated close

contacts of newly arrived international adopted children, most of

whom emanate from countries with intermediate-to-high hepatitis

A endemicity. Although hepatitis A is rarely bloodborne, several outbreaks have been recognized in recipients of clotting-factor concentrates. In the United States, the introduction of hepatitis A vaccination

programs among children from high-incidence states has resulted in

a >70% reduction in the annual incidence of new HAV infections and

has shifted the burden of new infections from children to adults. In the

2007–2012 U.S. Public Health Service National Health and Nutrition

Examination Survey (NHANES), the prevalence of anti-HAV in the

U.S. population aged ≥20 years had declined to 24.2% from the 29.5%

measured in NHANES 1999–2006. While universal childhood vaccination accounted for a high prevalence of vaccine-induced immunity

in children aged 2–19 years, the lowest age-specific prevalence of antiHAV (16.1–17.6%) occurred in adults in the fourth and fifth decades

(aged 30–49 years). This is a subgroup of the population who remain

susceptible to acute hepatitis A acquired during travel to endemic areas

and from contaminated foods, especially those imported from endemic

countries. Recognized initially in San Diego, California, in 2016, widespread person-to-person outbreaks, attributed to fecally contaminated

environments, of acute hepatitis A occurred primarily among homeless

persons and persons who were using injection drugs. Ultimately, this

outbreak extended to at least 32 states (highest number of cases in

Kentucky), and by March 2020, 31,950 cases were reported, resulting in

19,548 hospitalizations (61% of cases) and 322 deaths (1% of reported

cases, 1.6% of hospitalized cases). The increased clinical severity, rate of

hospitalization, and death in these outbreaks can be attributed to their

involving an older population (mean age ranging from 36 to 42 years),

born before the introduction of universal childhood hepatitis A vaccination and in whom clinical severity, as noted above, is higher than in

children. Moreover, the affected homeless and drug-using populations

suffer from multiple comorbidities (including HBV or HCV co-infection)

and disparities in access to health care. Addressing this multistate

outbreak has required a vigorous hepatitis A vaccination effort as well

as environmental sanitation/hygiene and education among these susceptible populations.

Hepatitis B Percutaneous inoculation has long been recognized

as a major route of hepatitis B transmission, but the outmoded designation “serum hepatitis” is an inaccurate label for the epidemiologic

spectrum of HBV infection. As detailed below, most of the hepatitis

transmitted by blood transfusion is not caused by HBV; moreover, in

approximately two-thirds of patients with acute type B hepatitis, no

history of an identifiable percutaneous exposure can be elicited. We

TABLE 339-2 Clinical and Epidemiologic Features of Viral Hepatitis

FEATURE HAV HBV HCV HDV HEV

Incubation (days) 15–45, mean 30 30–180, mean 60–90 15–160, mean 50 30–180, mean 60–90 14–60, mean 40

Onset Acute Insidious or acute Insidious or acute Insidious or acute Acute

Age preference Children, young

adults

Young adults (sexual and

percutaneous), babies,

toddlers

Any age, but more common

in adults

Any age (similar to HBV) Epidemic cases: young

adults (20–40 years);

sporadic cases: older

adults (>60)

Transmission

Fecal-oral

Percutaneous

Perinatal

Sexual

+++

Unusual

−

±

−

+++

+++

++

−

+++

±a

±a

−

+++

+

++

+++

−

−

−

Clinical

Severity

Fulminant

 Progression to chronicity

Carrier

Cancer

Prognosis

Mild

0.1%

None

None

None

Excellent

Occasionally severe

0.1–1%

Occasional (1–10%)

(90% of neonates)

0.1–30%f

 + (neonatal infection)

Worse with age, debility

Moderate

0.1%

Common (85%)

1.5–3.2%

+

Moderate

Occasionally severe

5–20%b

Commond

Variableg

±

Acute, good; chronic, poor

Mild

1–2%c

Nonee

None

None

Good

Prophylaxis Ig, inactivated

vaccine

HBIG, recombinant vaccine None HBV vaccine (none for

HBV carriers)

Vaccine

Therapy None Interferonh

Lamivudineh

Adefovirh

Pegylated interferoni

Entecaviri

Telbivudinei

Tenofovir disoproxil fumaratei

Tenofovir alafenamidei

Pegylated interferon ribavirin,h

telaprevir,h

 boceprevir,h

simeprevir,h

 sofosbuvir,

ledipasvir, paritaprevir/

ritonavir,h

 ombitasvir,h

dasabuvir,h

 daclatasvir,h

velpatasvir, grazoprevir,

elbasvir, glecaprevir,

pibrentasvir, voxilaprevir

Pegylated interferon ± Nonej

a

Primarily with HIV co-infection and high-level viremia in index case; more likely in persons with multiple sex partners or sexually transmitted diseases; risk ~5%. b

Up

to 5% in acute HBV/HDV co-infection; up to 20% in HDV superinfection of chronic HBV infection. e

10–20% in pregnant women. d

In acute HBV/HDV co-infection, the

frequency of chronicity is the same as that for HBV; in HDV superinfection, chronicity is invariable. e

Except as observed in immunosuppressed liver allograft recipients or

other immunosuppressed hosts. f

Varies considerably throughout the world and in subpopulations within countries; see text. g

Common in Mediterranean countries; rare in

North America and western Europe. h

No longer recommended or not included in first-line therapy. i

First-line agents. j

Anecdotal reports and retrospective studies suggest

that pegylated interferon and/or ribavirin are effective in treating chronic hepatitis E, observed in immunocompromised persons; ribavirin monotherapy has been used

successfully in acute, severe hepatitis E.

Abbreviation: HBIG, hepatitis B immunoglobulin. See text for other abbreviations.

2572 PART 10 Disorders of the Gastrointestinal System

now recognize that many cases of hepatitis B result from less obvious

modes of nonpercutaneous or covert percutaneous transmission.

HBsAg has been identified in almost every body fluid from infected

persons, and at least some of these body fluids—most notably semen

and saliva—are infectious, albeit less so than serum, when administered percutaneously or nonpercutaneously to experimental animals.

Among the nonpercutaneous modes of HBV transmission, oral

ingestion has been documented as a potential but inefficient route of

exposure. By contrast, the two nonpercutaneous routes considered to

have the greatest impact are intimate (especially sexual) contact and

perinatal transmission.

In sub-Saharan Africa, intimate contact among toddlers is considered instrumental in contributing to the maintenance of the high

frequency of hepatitis B in the population. Perinatal transmission

occurs primarily in infants born to mothers with chronic hepatitis B

or (rarely) mothers with acute hepatitis B during the third trimester of

pregnancy or during the early postpartum period. Perinatal transmission is uncommon in North America and western Europe but occurs

with great frequency and is the most important mode of HBV perpetuation in East Asia and developing countries. Although the precise

mode of perinatal transmission is unknown, and although ~10% of

infections may be acquired in utero, epidemiologic evidence suggests

that most infections occur approximately at the time of delivery and are

not related to breast-feeding (which is not contraindicated in women

with hepatitis B). The likelihood of perinatal transmission of HBV

correlates with the presence of HBeAg and high-level viral replication;

90% of HBeAg-positive mothers but only 10–15% of anti-HBe-positive

mothers transmit HBV infection to their offspring. In most cases, acute

infection in the neonate is clinically asymptomatic, but the child is very

likely to remain chronically infected.

The 250–290 million persons with chronic HBV infection in the

world constitute the main reservoir of hepatitis B in human beings.

Whereas serum HBsAg is infrequent (0.1–0.5%) in normal populations

in the United States and western Europe, a prevalence of up to 5–10%

has been found in East Asia, sub-Saharan Africa, and tropical countries; the prevalence can be even higher in certain high-risk groups,

including persons with Down’s syndrome, lepromatous leprosy, leukemia, Hodgkin’s disease, polyarteritis nodosa, and chronic renal disease

on hemodialysis, as well as in injection drug users.

Other groups with high rates of HBV infection include spouses of

acutely infected persons; sexually promiscuous persons (especially promiscuous men who have sex with men); health care workers exposed

to blood; persons who require repeated transfusions especially with

pooled blood-product concentrates (e.g., hemophiliacs); residents and

staff of custodial institutions for the developmentally handicapped;

prisoners; and, to a lesser extent, family members of chronically

infected patients. In volunteer blood donors, the prevalence of antiHBs, a reflection of previous HBV infection, ranges from 5 to 10%,

but the prevalence is higher in lower socioeconomic strata, older age

groups, and persons—including those mentioned above—exposed

to blood products. Because of highly sensitive virologic screening

(antigen, antibody, and nucleic acid testing) of donor blood, the risk

of acquiring HBV infection from a blood transfusion is 1 in 230,000

to 1 in 346,000.

Prevalence of infection, modes of transmission, and human behavior conspire to mold geographically different epidemiologic patterns

of HBV infection. In East Asia and Africa, hepatitis B, a disease of the

newborn and young children, is perpetuated by a cycle of maternalneonatal spread. In North America and western Europe, hepatitis B

is primarily a disease of adolescence and early adulthood, the time of

life when intimate sexual contact and recreational and occupational

percutaneous exposures tend to occur. To some degree, however, this

dichotomy between high-prevalence and low-prevalence geographic

regions has been minimized by immigration from high-prevalence

to low-prevalence areas. For example, in the United States, NHANES

data from 2007 to 2012 revealed an overall prevalence of current HBV

infection (detectable HBsAg) of 0.3%; however, the prevalence in Asian

persons, 93% of whom were foreign-born, was tenfold higher, 3.1%,

representing 50% of the U.S. national disease burden. As a result of

adoption of safe behaviors in high-risk groups as well as screening and

vaccination programs, the incidence of newly reported HBV infections

fell by >80% in the United States during the 1990s (with a low of 3050

reported cases in 2013). Paralleling that trend, the imbalance between

cases in U.S.-born and foreign-born persons widened; currently,

imported cases in non-U.S.-born persons outnumber domestic cases

by manyfold; in NHANES 1999–2016, the 2016 prevalence of HBV

infection was 0.24% in foreign-born versus 0.06% in U.S.-born persons;

in Asian persons, the 2016 prevalence of HBV infections was 3.85% in

foreign-born versus 0.79% in U.S.-born persons. The introduction of

hepatitis B vaccine in the early 1980s and adoption of universal childhood vaccination policies in many countries resulted in a dramatic,

~90% decline in the incidence of new HBV infections in those countries as well as in the dire consequences of chronic infection, including

hepatocellular carcinoma. In the United States, as demonstrated in

NHANES 2007–2012, following the 1991 implementation of universal

childhood vaccination, HBsAg seropositivity had declined in children

aged 6–19 years to as low as 0.03%, an ~85% reduction. Populations

and groups for whom HBV infection screening is recommended are

listed in Table 339-3.

Hepatitis D Infection with HDV has a worldwide distribution,

but two epidemiologic patterns exist. In Mediterranean countries

(northern Africa, southern Europe, the Middle East), HDV infection is

endemic among those with hepatitis B, and the disease is transmitted

predominantly by nonpercutaneous means, especially close personal

contact. In nonendemic areas, such as the United States (where

hepatitis D is rare among persons with chronic hepatitis B) and northern

Europe, HDV infection is confined to persons exposed frequently to

blood and blood products, primarily injection drug users (especially

in HIV-infected injection drug users) and hemophiliacs. In the United

States, the prevalence of HDV infection in the national population was

0.02% in NHANES 1999–2012 and 0.11% in NHANES 2011–2016;

however, among HBsAg-positive persons, the prevalence of HDV

infection is highest in injection drug users (11–36%) and hemophiliacs

(19%). HDV infection can be introduced into a population through

drug users or by migration of persons from endemic to nonendemic

areas. Thus, patterns of population migration and human behavior

facilitating percutaneous contact play important roles in the introduction and amplification of HDV infection. Occasionally, the migrating

epidemiology of hepatitis D is expressed in explosive outbreaks of

severe hepatitis, such as those that have occurred in remote South

American villages (e.g., “Lábrea fever” in the Amazon basin) as well

as in urban centers in the United States. Ultimately, such outbreaks

TABLE 339-3 High-Risk Populations for Whom HBV Infection

Screening Is Recommended

Persons born in countries/regions with a high (≥8%) and intermediate (≥2%)

prevalence of HBV infection including immigrants and adopted children and

including persons born in the United States who were not vaccinated as infants

and whose parents emigrated from areas of high HBV endemicity

Household and sexual contacts of persons with hepatitis B

Babies born to HBsAg-positive mothers

Persons who have used injection drugs

Persons with multiple sexual contacts or a history of sexually transmitted disease

Men who have sex with men

Inmates of correctional facilities

Persons with elevated alanine or aspartate aminotransferase levels

Blood/plasma/organ/tissue/semen donors

Persons with HCV or HIV infection

Hemodialysis patients

Pregnant women

Persons who are the source of blood or body fluids that would be an indication

for postexposure prophylaxis (e.g., needlestick, mucosal exposure, sexual

assault)

Persons who require immunosuppressive or cytotoxic therapy (including

anti–tumor necrosis factor α therapy for rheumatologic or inflammatory bowel

disorders)

2573Acute Viral Hepatitis CHAPTER 339

of hepatitis D—either of co-infections with acute hepatitis B or of

superinfections in those already infected with HBV—may blur the distinctions between endemic and nonendemic areas. On a global scale,

HDV infection declined at the end of the 1990s. Even in Italy, an HDVendemic area, public health measures introduced to control HBV

infection (e.g., mass hepatitis B vaccination) resulted during the 1990s

in a 1.5%/year reduction in the prevalence of HDV infection. Still, the

frequency of HDV infection during the first decade of the twentyfirst century has not fallen below levels reached during the 1990s; the

reservoir has been sustained by survivors infected during 1970–1980

and recent immigrants from still-endemic (e.g., eastern Europe and

Central Asia) to less-endemic countries. The current global prevalence

of HDV infection has been estimated at 62–72 million people. Of the

eight HDV genotypes, genotype 1 is distributed worldwide, while the

others are more geographically confined (e.g., genotypes 2 and 4 in

the Far East, 3 in South America, and 5–8 in Africa).

Hepatitis C Routine screening of blood donors for HBsAg and the

elimination of commercial blood sources in the early 1970s reduced the

frequency of, but did not eliminate, transfusion-associated hepatitis.

During the 1970s, the likelihood of acquiring hepatitis after transfusion

of voluntarily donated, HBsAg-screened blood was ~10% per patient

(up to 0.9% per unit transfused); 90–95% of these cases were classified,

based on serologic exclusion of hepatitis A and B, as “non-A, non-B”

hepatitis. For patients requiring transfusion of pooled products, such

as clotting factor concentrates, the risk was even higher, up to 20–30%.

During the 1980s, voluntary self-exclusion of blood donors with

risk factors for AIDS and then the introduction of donor screening

for anti-HIV reduced further the likelihood of transfusion-associated

hepatitis to <5%. During the late 1980s and early 1990s, the introduction first of “surrogate” screening tests for non-A, non-B hepatitis

(alanine aminotransferase [ALT] and anti-HBc, both shown to identify

blood donors with a higher likelihood of transmitting non-A, non-B

hepatitis to recipients) and, subsequently, after the discovery of HCV,

progressively more sensitive immunoassays for anti-HCV and then the

application of automated PCR testing of donated blood for HCV RNA

reduced the risk of transfusion-associated hepatitis C even further, to

almost imperceptible levels ranging between 1 in 2.3 million transfusions to 1 in 4.7 million transfusions.

In addition to being transmitted by transfusion, hepatitis C can

be transmitted by other percutaneous routes, such as injection drug

use. This virus can be transmitted by occupational exposure to blood,

and the likelihood of infection is increased in hemodialysis units. Although

the frequency of transfusion-associated hepatitis C fell as a result of

blood-donor screening, the overall frequency of reported hepatitis C

cases did not change until the 1990s, when the overall frequency of

reported cases fell by 80%, in parallel with a reduction in the number

of new cases in injection drug users, the source of most of the HCV

reservoir. After the exclusion of anti-HCV-positive plasma units from

the donor pool, rare, sporadic instances occurred of hepatitis C among

recipients of immunoglobulin preparations for intravenous (but not

intramuscular) use.

Serologic evidence for HCV infection occurs in 90% of patients

with a history of transfusion-associated hepatitis (almost all occurring

before 1992, when second-generation HCV screening tests were introduced); hemophiliacs and others treated with clotting factors; injection

drug users; 60–70% of patients with sporadic “non-A, non-B” hepatitis

who lack identifiable risk factors; 0.5% of volunteer blood donors;

and, in the NHANES survey conducted in the United States between

1999 and 2002, 1.6% of the general population in the United States,

which translated into 4.1 million persons (3.2 million with viremia),

the majority of whom were unaware of their infections. Moreover,

such population surveys do not include higher-risk groups such as

incarcerated persons, homeless persons, and active injection drug

users, indicating that the actual prevalence is even higher (estimated

to add an additional 1 million with anti-HCV antibody and 0.8 million

with HCV RNA in a later cohort assessed in 2003–2010). Comparable

frequencies of HCV infection occur in most countries around the

world, with 71 million persons infected worldwide, but extraordinarily

high prevalences of HCV infection occur in certain countries such as

Egypt, where >20% of the population (as high as 50% in persons born

prior to 1960) in some cities is infected. The high frequency in Egypt

is attributable to contaminated equipment used for medical procedures

and unsafe injection practices in the 1950s to 1980s (during a campaign

to eradicate schistosomiasis with intravenous tartar emetic). Thanks to

a 2018–2019 Egyptian government program to screen its entire adult

population (79% participation among >60 million people) for hepatitis

C and treat infected persons (2.2 million, 4.6% of those screened; of the

83% with a documented outcome, 99% were cured; the cost to identify

and cure a person was $130) with generic versions of direct-acting

antiviral (DAA) therapy (Chap. 341), hepatitis C has been nearly

eliminated there.

In the United States, African Americans and Mexican Americans

have higher frequencies of HCV infection than whites. Data from

NHANES showed that between 1988 and 1994, 30- to 40-year-old

men had the highest prevalence of HCV infection; however, in the

NHANES survey conducted between 1999 and 2002, the peak age

decile had shifted to those aged 40–49 years; an increase in hepatitis

C–related mortality has paralleled this secular trend, increasing since

1995 predominantly in the 45- to 65-year age group. Thus, despite an

80% reduction in new reported HCV infections during the 1990s, the

prevalence of HCV infection in the population was sustained by an

aging cohort that had acquired their infections three to four decades

earlier, during the 1960s and 1970s, as a result predominantly of selfinoculation with recreational drugs. Retrospective phylogenetic mapping

of >45,000 HCV genotype 1a isolates revealed that the hepatitis C epidemic emerged in the United States between 1940 and 1965, peaking in

1950 and aligning temporally with the post–World War II expansion of

medical procedures (including reuse of glass syringes). Thus, HCV was

amplified iatrogenically not only in Egypt but also in the United States;

in the United States, the seeds sewn by medical procedures in the 1950s

were reaped in the 1960s and 1970s among transfusion recipients and

injection drug users, even those whose drug use was confined to brief

adolescent experimentation.

In NHANES 2003–2010, the prevalence of HCV infection (HCV

RNA reactivity) in the United States had actually fallen to 1% (2.7

million persons) from 1.3% (3.2 million) the decade before (NHANES

1999–2002), attributable to deaths among the HCV-infected population. In NHANES data from 2010–2014, the prevalence of current

HCV infection (HCV RNA reactivity) had fallen even lower, to 0.65%

(1.7 million persons), coinciding with and attributable to the introduction of highly effective, oral DAA drugs (Chap. 341). As deaths

resulting from HIV infection fell after 1999, age-adjusted mortality

associated with HCV infection surpassed that of HIV infection in 2007;

>70% of HCV-associated deaths occurred in the “baby boomer” cohort

born between 1945 and 1965. By 2012, HCV mortality had surpassed

deaths from HIV, tuberculosis, hepatitis B, and 57 other notifiable

infectious diseases (i.e., all infectious diseases) reported to the CDC. In

NHANES 1999–2002, compared to the 1.6% prevalence of HCV infection in the population at large, the prevalence in the 1945–1965 birth

cohort was 3.2%, representing three-quarters of all infected persons.

Therefore, in 2012, the CDC and, in 2013, the U.S. Preventive Services

Task Force (USPSTF) recommended that all persons born between

1945 and 1965 be screened for hepatitis C, without ascertainment of

risk, a recommendation shown to be cost-effective and predicted to

identify 800,000 infected persons. Because of the availability of highly

effective antiviral therapy, such screening would have the potential to

avert 200,000 cases of cirrhosis and 47,000 cases of hepatocellular carcinoma and to prevent 120,000 hepatitis-related deaths; with the availability of the new generation of DAAs (efficacy >95%, see Chap. 341),

screening baby boomers and treating those with hepatitis C have been

predicted to reduce the HCV-associated disease burden by 50–70%

through 2050.

Still, persons with chronic hepatitis C identified by 1945–1965

birth-cohort screening are older than 50, and by the time they are identified, >20% already have advanced liver disease. In 2020, based on (1)

the 95–99% efficacy of all-oral, well-tolerated, highly effective DAAs;

(2) the demonstration that the endpoint of DAA therapy (sustained

2574 PART 10 Disorders of the Gastrointestinal System

virologic response) was associated with a marked decrease in liver and

all-cause mortality, cirrhosis, and hepatocellular carcinoma (Chap. 341);

(3) a reduction in the initially high cost of DAA therapy; (4) the

demonstration of higher cost-effectiveness of screening all adults

rather than birth-cohort screening; and (5) the shifting demographics

of HCV infection (see below), especially since 2010, toward a younger

population exposed through injection drug use, the American Association for the Study of Liver Diseases and the Infectious Diseases Society

of America as well as the USPSTF and CDC expanded recommended

hepatitis C screening to all adolescents and adults aged 18–79 (and

because of the substantial increase in HCV infections among women

of child-bearing age [age 20–39], expanded such screening to pregnant

women).

Hepatitis C accounts for 40% of chronic liver disease and, before

the introduction of high-efficacy DAA therapy, was the most frequent indication for liver transplantation; hepatitis C is estimated to

account for 8000–10,000 deaths per year in the United States. The

distribution of HCV genotypes varies in different parts of the world.

Worldwide, genotype 1 is the most common. In the United States,

genotype 1 accounts for 70% of HCV infections, whereas genotypes 2

and 3 account for the remaining 30%; among African Americans, the

frequency of genotype 1 is even higher (i.e., 90%). Genotype 4 predominates in Egypt; genotype 5 is localized to South Africa, genotype

6 to Hong Kong, and genotype 7 to Central Africa. Most asymptomatic

blood donors found to have anti-HCV and ~20–30% of persons with

reported cases of acute hepatitis C do not fall into a recognized risk

group; however, many such blood donors do recall risk-associated

behaviors when questioned carefully.

As a bloodborne infection, HCV potentially can be transmitted

sexually and perinatally; however, both modes of transmission are

inefficient for hepatitis C. Although 10–15% of patients with acute

hepatitis C report having potential sexual sources of infection, most

studies have failed to identify sexual transmission of this agent. The

chances of sexual and perinatal transmission have been estimated to

be ~5% but have shown in a prospective study to be only 1% between

monogamous sexual partners, well below comparable rates for HIV

and HBV infections. Moreover, sexual transmission appears to be confined to such subgroups as persons with multiple sexual partners and

sexually transmitted diseases; for example, isolated clusters of sexually

transmitted HCV infection have been reported in HIV-infected men

who have sex with men. Breast-feeding does not increase the risk of

HCV infection between an infected mother and her infant. Infection

of health workers is not dramatically higher than among the general

population; however, health workers are more likely to acquire HCV

infection through accidental needle punctures, the efficiency of which

is ~3%. Infection of household contacts is rare as well.

Besides persons born between 1945 and 1965, other groups with

an increased frequency of HCV infection are listed in Table 339-4. In

immunosuppressed individuals, levels of anti-HCV may be undetectable, and a diagnosis may require testing for HCV RNA. Although new

acute cases of hepatitis C are rare outside of the injection drug–using

community, newly diagnosed cases are common among otherwise

healthy persons who experimented briefly with injection drugs, as

noted above, four or five decades earlier. Such instances usually remain

unrecognized for years, until unearthed by laboratory screening for

routine medical examinations, insurance applications, and attempted

blood donation. Although, overall, the annual incidence of new

HCV infections has continued to fall, the rate of new infections has

been increasing since 2002, has accelerated since 2010 (tripling from

0.3/100,000 to 1.2/100,000 between 2009 and 2018), and has been

amplified by the recent epidemic of opioid use in a new cohort of

young injection drug users aged 20–39 years (accounting for a 3.8-fold

increase in cases between 2010 and 2017 and for more than two-thirds

of all acute cases), who, unlike older cohorts, had not learned to take

precautions to prevent bloodborne infections. Reflecting this emerging

development, the prevalence of current HCV infection (HCV RNA

reactivity) in the United States rose from 0.65% (1.7 million persons)

in a 2010–2014 NHANES analysis to 0.84% (2.04 million persons)

in a 2013–2014 NHANES analysis. Moreover, based on an estimate

of populations excluded from this NHANES analysis, the prevalence

would be even higher, 0.93% (2.27 million persons). This late temporal trend was attributed to the increase of acute cases in injections

drug users, driven by increases in states most affected by the opioid/

injection drug use epidemic. Also, in parallel with this trend, the prevalence of HCV infection in women aged 15–44 years (of child-bearing

age) doubled between 2016 and 2014; accordingly, screening of pregnant women for HCV infection is now recommended as well.

Hepatitis E This type of hepatitis, identified in India, Asia, Africa,

the Middle East, and Central America (endemic areas), resembles

hepatitis A in its primarily enteric mode of spread. The commonly

recognized cases occur after contamination of water supplies such as

after monsoon flooding, but sporadic, isolated cases occur. An epidemiologic feature that distinguishes HEV from other enteric agents is

the rarity of secondary person-to-person spread from infected persons

to their close contacts. Large waterborne outbreaks in endemic areas

are linked to genotypes 1 and 2, arise in populations that are immune

to HAV, favor young adults, and account for antibody prevalences of

30–80%. The worldwide annual incidence of acute HEV infections

has been estimated conservatively to be at least 20 million (of which

3.3 million are symptomatic), rendering HEV infection as the most

common cause of acute viral hepatitis. In nonendemic areas of the

world, such as the United States, clinically apparent acute hepatitis E is

extremely rare; however, during the 1988–1994 NHANES survey conducted by the U.S. Public Health Service, the prevalence of anti-HEV

was 21%, reflecting subclinical infections, infection with genotypes 3

and 4, predominantly in older males (>60 years). A repeat NHANES

study in 2009–2010, however, showed a substantial 70% two-decade

reduction in anti-HEV to only 6%, more consistent with the rarity of

acute hepatitis E in the United States than the previous NHANES result

would suggest and perhaps a reflection of a more specific anti-HEV

assay used in the second time period. Again, older age was associated

with anti-HEV seropositivity. In nonendemic areas, HEV accounts for

only a small proportion of cases of sporadic (labeled “autochthonous”

or indigenous) hepatitis; however, cases imported from endemic areas

have been found in the United States. Evidence supports a zoonotic

reservoir for HEV primarily in swine (but also in deer, camels, and

rabbits), which may account for the mostly subclinical infections primarily of genotypes 3 and 4 in nonendemic areas. A previously unrecognized high distribution of HEV infection, linked to uncooked or

undercooked pork-product ingestion, has been discovered in western

Europe (e.g., in Germany, an estimated annual incidence of 300,000

cases and a 17% prevalence of anti-HEV among adults; in France, a

22% prevalence of anti-HEV in healthy blood donors).

■ CLINICAL AND LABORATORY FEATURES

Symptoms and Signs Acute viral hepatitis occurs after an incubation period that varies according to the responsible agent. Generally,

incubation periods for hepatitis A range from 15 to 45 days (mean,

TABLE 339-4 High-Risk Populations for Whom HCV-Infection

Screening Is Recommended

All adults aged 18–79 should be screened, a recommendation that supplants the

earlier focus on persons born between 1945 and 1965

Persons who have ever used injection drugs

Persons with HIV infection

Hemophiliacs treated with clotting factor concentrates prior to 1987

Persons who have ever undergone long-term hemodialysis

Persons with unexplained elevations of aminotransferase levels

Transfusion or transplantation recipients prior to July 1992

Recipients of blood or organs from a donor found to be positive for hepatitis C

Children born to women with hepatitis C

Health care, public safety, and emergency medical personnel following needle

injury or mucosal exposure to HCV-contaminated blood

Sexual partners of persons with hepatitis C infection

Pregnant women

2575Acute Viral Hepatitis CHAPTER 339

4 weeks), for hepatitis B and D from 30 to 180 days (mean, 8–12 weeks),

for hepatitis C from 15 to 160 days (mean, 7 weeks), and for hepatitis

E from 14 to 60 days (mean, 5–6 weeks). The prodromal symptoms of

acute viral hepatitis are systemic and quite variable. Constitutional

symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza

may precede the onset of jaundice by 1–2 weeks. The nausea, vomiting,

and anorexia are frequently associated with alterations in olfaction and

taste. A low-grade fever between 38° and 39°C (100°–102°F) is more

often present in hepatitis A and E than in hepatitis B or C, except when

hepatitis B is heralded by a serum sickness–like syndrome; rarely, a

fever of 39.5°–40°C (103°–104°F) may accompany the constitutional

symptoms. Dark urine and clay-colored stools may be noticed by the

patient from 1–5 days before the onset of clinical jaundice.

With the onset of clinical jaundice, the constitutional prodromal

symptoms usually diminish, but in some patients, mild weight loss

(2.5–5 kg) is common and may continue during the entire icteric phase.

The liver becomes enlarged and tender and may be associated with

right upper quadrant pain and discomfort. Infrequently, patients present with a cholestatic picture, suggesting extrahepatic biliary obstruction. Splenomegaly and cervical adenopathy are present in 10–20%

of patients with acute hepatitis. Rarely, a few spider angiomas appear

during the icteric phase and disappear during convalescence. During

the recovery phase, constitutional symptoms disappear, but usually

some liver enlargement and abnormalities in liver biochemical tests are

still evident. The duration of the posticteric phase is variable, ranging

from 2 to 12 weeks, and is usually more prolonged in acute hepatitis B

and C. Complete clinical and biochemical recovery is to be expected

1–2 months after all cases of hepatitis A and E and 3–4 months after the

onset of jaundice in three-quarters of uncomplicated, self-limited cases

of hepatitis B and C (among healthy adults, acute hepatitis B is self-limited in 95–99%, whereas hepatitis C is self-limited in only ~15–20%).

In the remainder, biochemical recovery may be delayed. A substantial

proportion of patients with viral hepatitis never become icteric.

Infection with HDV can occur in the presence of acute or chronic

HBV infection; the duration of HBV infection determines the duration of HDV infection. When acute HDV and HBV infections occur

simultaneously, clinical and biochemical features may be indistinguishable from those of HBV infection alone, although occasionally, they

are more severe. As opposed to patients with acute HBV infection,

patients with chronic HBV infection can support HDV replication

indefinitely, as when acute HDV infection occurs in the presence of

a nonresolving acute HBV infection or, more commonly, when acute

hepatitis D is superimposed on underlying chronic hepatitis B. In such

cases, the HDV superinfection appears as a clinical exacerbation or an

episode resembling acute viral hepatitis in someone already chronically

infected with HBV. Superinfection with HDV in a patient with chronic

hepatitis B often leads to clinical deterioration (see below).

In addition to superinfections with other hepatitis agents, acute

hepatitis-like clinical events in persons with chronic hepatitis B may

accompany spontaneous HBeAg to anti-HBe seroconversion or spontaneous reactivation (i.e., reversion from relatively nonreplicative to

replicative infection). Such reactivations can occur as well in therapeutically immunosuppressed patients with chronic HBV infection

when cytotoxic/immunosuppressive drugs are withdrawn; in these

cases, restoration of immune competence is thought to allow resumption of previously checked cell-mediated immune cytolysis of HBVinfected hepatocytes. Occasionally, acute clinical exacerbations of

chronic hepatitis B may represent the emergence of a precore mutant

(see “Virology and Etiology”), and the subsequent course in such

patients may be characterized by periodic exacerbations. Cytotoxic

chemotherapy can lead to reactivation of chronic hepatitis C as well,

and treatment with other immunomodulators, such as monoclonal

antibodies against anti-TNF-α and other cytokines and especially the

B-cell (CD20)–depleting antibody rituximab, can lead to reactivation

of both hepatitis B and C.

Laboratory Features The serum aminotransferases aspartate

aminotransferase (AST) and ALT (previously designated SGOT and

SGPT) increase to a variable degree during the prodromal phase of

acute viral hepatitis and precede the rise in bilirubin level (Figs. 339-2

and 339-4). The level of these enzymes, however, does not correlate

well with the degree of liver cell damage. Peak levels vary from ~400

to ~4000 IU or more; these levels are usually reached at the time the

patient is clinically icteric and diminish progressively during the recovery phase of acute hepatitis. The diagnosis of anicteric hepatitis is based

on clinical features and on aminotransferase elevations.

Jaundice is usually visible in the sclera or skin when the serum bilirubin value is >43 μmol/L (2.5 mg/dL). When jaundice appears, the

serum bilirubin typically rises to levels ranging from 85 to 340 μmol/L

(5–20 mg/dL). The serum bilirubin may continue to rise despite falling

serum aminotransferase levels. In most instances, the total bilirubin is

equally divided between the conjugated and unconjugated fractions.

Bilirubin levels >340 μmol/L (20 mg/dL) extending and persisting late

into the course of viral hepatitis are more likely to be associated with

severe disease. In certain patients with underlying hemolytic anemia,

however, such as glucose-6-phosphate dehydrogenase deficiency and

sickle cell anemia, a high serum bilirubin level is common, resulting from superimposed hemolysis. In such patients, bilirubin levels

>513 μmol/L (30 mg/dL) have been observed and are not necessarily

associated with a poor prognosis.

Neutropenia and lymphopenia are transient and are followed by a

relative lymphocytosis. Atypical lymphocytes (varying between 2 and

20%) are common during the acute phase. Measurement of the prothrombin time (PT) is important in patients with acute viral hepatitis,

because a prolonged value may reflect a severe hepatic synthetic defect,

signify extensive hepatocellular necrosis, and indicate a worse prognosis. Occasionally, a prolonged PT may occur with only mild increases in

the serum bilirubin and aminotransferase levels. Prolonged nausea and

vomiting, inadequate carbohydrate intake, and poor hepatic glycogen

reserves may contribute to hypoglycemia noted occasionally in patients

with severe viral hepatitis. Serum alkaline phosphatase may be normal

or only mildly elevated, whereas a fall in serum albumin is uncommon

in uncomplicated acute viral hepatitis. In some patients, mild and

transient steatorrhea has been noted, as well as slight microscopic

hematuria and minimal proteinuria.

A diffuse but mild elevation of the γ globulin fraction is common

during acute viral hepatitis. Serum IgG and IgM levels are elevated in

about one-third of patients during the acute phase of viral hepatitis,

but the serum IgM level is elevated more characteristically during

acute hepatitis A. During the acute phase of viral hepatitis, antibodies

to smooth muscle and other cell constituents may be present, and low

titers of rheumatoid factor, nuclear antibody, and heterophile antibody

can also be found occasionally. In hepatitis C and D, antibodies to

LKM may occur; however, the species of LKM antibodies in the two

types of hepatitis are different from each other as well as from the

LKM antibody species characteristic of autoimmune hepatitis type 2

(Chap. 341). The autoantibodies in viral hepatitis are nonspecific and

can also be associated with other viral and systemic diseases. In contrast, virus-specific antibodies, which appear during and after hepatitis

virus infection, are serologic markers of diagnostic importance.

As described above, serologic tests are available routinely with

which to establish a diagnosis of hepatitis A, B, D, and C. Tests for fecal

or serum HAV are not routinely available. Therefore, a diagnosis of

hepatitis A is based on detection of IgM anti-HAV during acute illness

(Fig. 339-2). Rheumatoid factor can give rise to false-positive results

in this test.

A diagnosis of HBV infection can usually be made by detection

of HBsAg in serum. Infrequently, levels of HBsAg are too low to be

detected during acute HBV infection, even with contemporary, highly

sensitive immunoassays. In such cases, the diagnosis can be established

by the presence of IgM anti-HBc.

The titer of HBsAg bears little relation to the severity of clinical

disease. Indeed, an inverse correlation exists between the serum concentration of HBsAg and the degree of liver cell damage. For example,

titers are highest in immunosuppressed patients, lower in patients with

chronic liver disease (but higher in mild chronic than in severe chronic

hepatitis), and very low in patients with acute fulminant hepatitis.