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Viral Hepatitis
Updated: Jul 07, 2023
Author: Naga Swetha Samji, MD; Chief Editor: BS Anand, MD more...

OVERVIEW

Background
Hepatitis, a general term referring to inflammation of the liver, may result from various
causes, both infectious (ie, viral, bacterial, fungal, and parasitic organisms) and
noninfectious (eg, alcohol, drugs, autoimmune diseases, and metabolic diseases); this
article focuses on viral hepatitis, which accounts for more than 50% of cases of acute
hepatitis in the United States, primarily in the emergency department setting.

In the United States, viral hepatitis is most commonly caused by hepatitis A virus (HAV),
hepatitis B virus (HBV), and hepatitis C virus (HCV). These three viruses can all result in
acute disease with symptoms of nausea, abdominal pain, fatigue, malaise, and jaundice. [1]
Additionally, acute infection with HBV and HCV can lead to chronic infection. Patients who
are chronically infected may go on to develop cirrhosis and hepatocellular carcinoma (HCC).
[1] Furthermore, chronic hepatitis carriers remain infectious and may transmit the disease for

many years. [2]

Other hepatotropic viruses known to cause hepatitis include hepatitis D virus (HDV) and
hepatitis E virus (HEV). However, the term hepatotropic is itself a misnomer. Infections with
hepatitis viruses, especially HBV and HBC, have been associated with a wide variety of
extrahepatic manifestations. Infrequent causes of viral hepatitis include adenovirus,
cytomegalovirus (CMV), Epstein-Barr virus (EBV) and, rarely, herpes simplex virus (HSV).
Other pathogens (eg, virus SEN-V) may account for additional cases of non-A/non-E
hepatitis.

Acute versus chronic viral hepatitis

The term viral hepatitis can describe either a clinical illness or the histologic findings
associated with the disease. Acute infection with a hepatitis virus may result in conditions
ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic
failure. Adults with acute hepatitis A or B are usually symptomatic. Persons with acute
hepatitis C may be either symptomatic or asymptomatic (ie, subclinical).

Typical symptoms of acute hepatitis are fatigue, anorexia, nausea, and vomiting. Very high
aminotransferase values (>1000 U/L) and hyperbilirubinemia are often observed. Severe
cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic
synthetic function. This is often defined as a prothrombin time (PT) of 16 seconds or more
and an international normalized ratio (INR) of 1.5 or more in the absence of previous liver
disease.

Fulminant hepatic failure (FHF) is defined as acute liver failure that is complicated by
hepatic encephalopathy. In contrast to the encephalopathy associated with cirrhosis, the
encephalopathy of FHF is attributed to increased permeability of the blood-brain barrier and
to impaired osmoregulation in the brain, which leads to brain-cell swelling. The resulting
brain edema is a potentially fatal complication of fulminant hepatic failure.

FHF may occur in as many as 1% of cases of acute hepatitis due to hepatitis A or B.

Hepatitis E is a common cause in Asia; whether hepatitis C is a cause remains
controversial. Although FHF may resolve, more than half of all cases result in death unless
liver transplantation is performed in time.

Providing that acute viral hepatitis does not progress to FHF, many cases resolve over a
period of days, weeks, or months. Acute HBV infection is generally considered resolved
once an individual has developed antibodies to the hepatitis B surface antigen (anti-HBs)
and has cleared hepatitis B surface antigen (HBsAg) from their serum. [3] Alternatively, acute
viral hepatitis may evolve into chronic hepatitis. HBV infection is considered to have
progressed to chronic infection when HBsAg, hepatitis B e antigen (HBeAg), and high titers
of hepatitis B viral DNA are found to persist in the serum for longer than 6 months. [3, 4, 5]
Hepatitis C infection is considered to have progressed to chronic infection when HCV RNA
persists in the blood for longer than 6 months. [6, 7] Hepatitis A and hepatitis E never
progress to chronic hepatitis, either clinically or histologically.

The likelihood of progressing to chronic hepatitis B infection varies with the age at the time
of infection. Chronic hepatitis B infection develops in up to 90% of individuals infected as
neonates; however only 1-5% of individuals infected with HBV as adults develop chronic
hepatitis B infection. [3] Chronic hepatitis C infection develops in 75-85% of patients infected
with hepatitis C. [6] Individuals infected with HCV at a younger age are less likely to develop
chronic hepatitis C infection. [6] Some patients with chronic hepatitis remain asymptomatic
for their entire lives. Other patients report fatigue (ranging from mild to severe) and
dyspepsia.

Individuals with chronic hepatitis B or hepatitis C infection may go on to develop cirrhosis,

with histologic changes of severe fibrosis and nodular regeneration. In their study of
serologic markers in patients with cirrhosis and hepatocellular carcinoma, Perz et al
estimated that 57% of cirrhosis and 78% of hepatocellular carcinoma worldwide was
attributable to chronic infection with either hepatitis B or C. [8]

Although some patients with cirrhosis are asymptomatic, others develop life-threatening
complications. The clinical illnesses of chronic hepatitis and cirrhosis may take months,
years, or decades to evolve.

Pathophysiology
Hepatitis A
The incubation period of hepatitis A virus (HAV) is 15-45 days (average, 4 weeks). The virus
is excreted in stool during the first few weeks of infection, before the onset of symptoms.
Young children who are infected with HAV usually remain asymptomatic. Acute hepatitis A is
more severe and has higher mortality in adults than in children. The explanation for this is
unknown.

Typical cases of acute HAV infection are marked by several weeks of malaise, anorexia,
nausea, vomiting, and elevated aminotransferase levels. Jaundice develops in more severe
cases. Some patients experience a cholestatic hepatitis, marked by the development of an
elevated alkaline phosphatase (ALP) level, in contrast to the classic picture of elevated
aminotransferase levels. Other patients may experience several relapses during the course
of a year. Less than 1% of cases result in fulminant hepatic failure (FHF). HAV infection
does not persist and does not lead to chronic hepatitis.

Hepatitis B
Hepatitis B virus (HBV) may be directly cytopathic to hepatocytes. However, immune
system–mediated cytotoxicity plays a predominant role in causing liver damage. The
immune assault is driven by human leukocyte antigen (HLA) class I–restricted CD8 cytotoxic
T lymphocytes that recognize hepatitis B core antigen (HBcAg) and hepatitis B e antigen
(HBeAg) on the cell membranes of infected hepatocytes.

Acute infection

The incubation period of HBV infection is 40-150 days (average, approximately 12 weeks).
As with acute HAV infection, the clinical illness associated with acute HBV infection may
range from mild disease to a disease as severe as FHF (< 1% of patients). After acute
hepatitis resolves, 95% of adult patients and 5-10% of infected infants ultimately develop
antibodies against hepatitis B surface antigen (HBsAg)—that is, anti-HBs—clear HBsAg
(and HBV virions), and fully recover. About 5% of adult patients, 90% of infected infants, and
30-50% of children infected at age 1-5 years develop chronic infection. [9]

Some patients, particularly individuals who are infected as neonates or as young children,
have elevated serum levels of HBV DNA and a positive blood test for the presence of
HBeAg but have normal alanine aminotransferase (ALT) levels and show minimal histologic
evidence of liver damage. These individuals are in the so-called "immune-tolerant phase" of
disease. [10, 11] Years later, some but not all of these individuals may enter the "immune-
active phase" of disease, in which the HBV DNA may remain elevated as the liver
experiences active inflammation and fibrosis. An elevated ALT level is also noted during this
period. Typically, the immune-active phase ends with the loss of HBeAg and the
development of antibodies to HBeAg (anti-HBe). [10, 11]

Individuals who seroconvert from an HBeAg-positive state to an HBeAg-negative state may

enter the "inactive carrier state" (previously known as the "healthy carrier state"). Such
individuals are asymptomatic, have normal liver chemistry test results, and have normal or
minimally abnormal liver biopsy results. Blood test evidence of HBV replication should be
nonexistent or minimal, with a serum HBV DNA level in the range of 0 to 2000 IU/mL. [10, 12]

Inactive carriers remain infectious to others through parenteral or sexual transmission.

Inactive carriers may ultimately develop anti-HBs and clear the virus. However, some
inactive carriers develop chronic hepatitis, as determined by liver chemistry results, liver
biopsy findings, and HBV DNA levels. Inactive carriers remain at risk for hepatocellular
carcinoma (HCC), although the risk is low. At this point, no effective antiviral therapies are
available for patients in an inactive carrier state.

Other patients who seroconvert may enter the "reactivation phase" of disease. These
individuals remain HBeAg-negative but have serum HBV DNA levels higher than 2000
IU/mL and show evidence of active liver inflammation. These patients are said to have
HBeAg-negative chronic hepatitis. [10]

Chronic infection

The 10-30% of HBsAg carriers who develop chronic hepatitis are often symptomatic.
Fatigue is the most common symptom of chronic hepatitis B. Acute disease flares
occasionally occur, with symptoms and signs similar to those of acute hepatitis. Extrahepatic
manifestations of the disease (eg, polyarteritis nodosa, cryoglobulinemia, and
glomerulonephritis) may develop. Chronic hepatitis B patients have abnormal liver chemistry
results, blood test evidence of active HBV replication, and inflammatory or fibrotic activity on
liver biopsy specimens (see the images below).
Viral Hepatitis. Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Viral Hepatitis. Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis
B.

Patients with chronic hepatitis may be considered either HBeAg-positive or HBeAg-negative.

In North America and Northern Europe, about 80% of chronic hepatitis B cases are HBeAg
positive and 20% HBeAg negative. In Mediterranean countries and in some parts of Asia,
30-50% of cases are HBeAg positive and 50-80% HBeAg negative.

Patients with HBeAg-positive chronic hepatitis have signs of active viral replication, with an
HBV DNA level greater than 2 × 104 IU/mL. [10, 12] HBV DNA levels may be as high as 1011
IU/mL.

Patients with HBeAg-negative chronic hepatitis were presumably infected with wild-type
virus at some point. Over time, they acquired a mutation in either the precore or the core
promoter region of the viral genome. In such patients with a precore mutant state, HBV
continues to replicate, but HBeAg is not produced. Patients with a core mutant state appear
to have downregulated HBeAg production. [13]

The vast majority of patients with HBeAg-negative chronic hepatitis B have a serum HBV
DNA level greater than 2000 IU/mL. Typically, HBeAg-negative patients have lower HBV
DNA levels than HBeAg-positive patients do. Commonly, the HBV DNA level is no higher
than 2 × 104 IU/mL. [10, 12]

HBV and HCC

An approximately 8-20% of untreated adults with chronic hepatitis B go on to develop

cirrhosis within 5 years; of these individuals, 20% annually develop hepatic decompensation
and 2-5% annually develop HCC (see the image below). [5, 9] Globally, an estimated 30% of
cases of cirrhosis and 45% of cases of HCC are attributed to HBV. [5] The incidence of HCC
parallels the incidence of HBV infection in various countries around the world. Worldwide, up
to 1 million cases of HCC are diagnosed each year. Most appear to be related to HBV
infection.

Viral Hepatitis. Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma in an 80-year-old man
without cirrhosis.

In HBV-induced cirrhosis, as in cirrhosis due to other causes, hepatic inflammation and

regeneration appear to stimulate mutational events and carcinogenesis. However, in HBV
infection, in contrast to other liver diseases, the presence of cirrhosis is not a prerequisite for
the development of HCC. The integration of HBV into the hepatocyte genome may lead to
the activation of oncogenes or the inhibition of tumor suppressor genes. As an example,
mutations or deletions of the p53 and RB tumor suppressor genes are seen in many cases
of HCC. [14]

Multiple studies have demonstrated an association between elevated serum HBV DNA
levels and an increased risk for the development of HCC. [15] Conversely, successful
suppression of HBV infection by antiviral therapy can decrease the risk of developing HCC.
[16, 17]

HCC is a treatable and potentially curable disease, whether the treatment entails tumor
ablation (eg, with percutaneous injection of ethanol into the tumor), liver resection, or liver
transplantation. The American Association for the Study of Liver Diseases (AASLD) and the
World Health Organization (WHO) recommend screening for HBV-infected individuals who
are at high risk for HCC, including men older than 40 years, individuals with HBV-induced
cirrhosis, and persons with a family history of HCC. [4, 5, 12]

For these patients, ultrasonography of the liver and alpha-fetoprotein (AFP) testing every 6
months are recommended. No specific recommendations have been made for patients at
low risk for HCC. Some clinicians recommend that low-risk patients (including inactive
carriers) undergo only AFP and liver chemistry testing every 6 months. Other clinicians’
practice is to screen all chronic hepatitis B patients with ultrasonography and AFP testing
every 6 months, with inactive carriers undergoing liver chemistry and AFP testing every 6
months; however, this is controversial.

Hepatitis C
HCV has a viral incubation period of approximately 8 weeks. Most cases of acute HCV
infection are asymptomatic. Even when it is symptomatic, acute HCV infection tends to
follow a mild course, with aminotransferase levels rarely higher than 1000 U/L. Whether
acute HCV infection is a cause of FHF remains controversial.

Approximately 15-45% of patients acutely infected with HCV lose virologic markers for HCV.
Thus, about 55-85% of newly infected patients remain viremic and may develop chronic liver
disease. [18] In chronic hepatitis C, patients may or may not be symptomatic, with fatigue
being the predominant reported symptom. Aminotransferase levels may range from
reference values (< 40 U/L) to values as high as 300 U/L. However, no clear-cut association
exists between aminotransferase levels and symptoms or the risk of disease progression.

An estimated 15-30% of patients with chronic hepatitis C experience progression to

cirrhosis. [18] This process may take decades. All patients who are newly diagnosed with
well-compensated cirrhosis must be counseled regarding their risk of developing symptoms
of liver failure (ie, decompensated cirrhosis). Only 30% of patients with well-compensated
cirrhosis are anticipated to decompensate over a 10-year follow-up period.

Patients with HCV-induced cirrhosis are also at increased risk for the development of HCC
(see the image below), especially in the setting of HBV coinfection. In the United States,
HCC arises in 1-5% of patients with HCV-induced cirrhosis each year. [19] Accordingly,
routine screening (eg, ultrasonography and AFP testing every 6 months) is recommended in
patients with HCV-induced cirrhosis to rule out the development of HCC. [7, 20] Nearly
20,000 deaths each year are attributable to HCV as an underlying or contributing cause of
death. [19]
Viral Hepatitis. Triple-phase computed tomography scan depicting liver cancer, revealing classic findings of
enhancement during the arterial phase and delayed hypointensity during the portal venous phase.

Hepatitis D
Simultaneous introduction of HBV and HDV into a patient results in the same clinical picture
as acute infection with HBV alone. The resulting acute hepatitis may be mild or severe.
Similarly, the risk of developing chronic HBV and HDV infection after acute exposure to both
viruses is the same as the rate of developing chronic HBV infection after acute exposure to
HBV (approximately 5% in adults [5] ). However, chronic HBV and HDV disease tends to
progress more rapidly to cirrhosis than chronic HBV infection alone does. [5]

Introduction of HDV into an individual already infected with HBV may have dramatic
consequences. Superinfection may give HBsAg-positive patients the appearance of a
sudden worsening or flare of hepatitis B. HDV superinfection may result in FHF. [5]

Hepatitis E
HEV has an incubation period of 2-10 weeks. [21] Acute HEV infection is generally less
severe than acute HBV infection and is characterized by fluctuating aminotransferase levels.
However, pregnant women, especially when infected during the third trimester, have a
greater than 25% risk of mortality associated with acute HEV infection. [22] In a number of
cases, FHF caused by HEV has necessitated liver transplantation.

Traditionally, HEV was not believed to cause chronic liver disease. However, several reports
have described chronic hepatitis due to HEV in organ transplant recipients. [23] Liver
histology revealed dense lymphocytic portal infiltrates with interface hepatitis, similar to the
findings seen with hepatitis C infection. Some cases have progressed to cirrhosis. [24, 25]

Etiology
Hepatitis viruses A, B, C, D (HAV, HBV, HCV, HDV [which requires coexisting HBV
infection]), and E (HEV) cause the majority of clinical cases of viral hepatitis. Whether
hepatitis G virus (HGV) is pathogenic in humans remains unclear. HAV, HBV, HCV, and HDV
are the only hepatitis viruses endemic to the United States; HAV, HBV, and HCV are
responsible for more than 90% of US cases of acute viral hepatitis. Whereas HAV and HBV
are the most common causes of acute hepatitis in the United States, HCV is the most
common cause of chronic hepatitis. [26]

The following are typical patterns by which hepatitis viruses are transmitted, with + symbols
indicating the frequency of transmission (ie, more + symbols indicate increased frequency).

Fecal-oral transmission frequency is as follows:

HAV (+++)

HEV (+++)

Parenteral transmission frequency is as follows:

HBV (+++)

HCV (+++)

HDV (++)

HGV (++)

HAV (+)

Sexual transmission frequency is as follows:

HBV (+++)

HDV (++)

HCV (+)

Perinatal transmission frequency is as follows:

HBV (+++)

HCV (+)

HDV (+)

Sporadic (unknown) transmission frequency is as follows:

HBV (+)

HCV (+)

Hepatitis A
HAV (see the image below), a member of the Picornaviridae family, is an RNA virus with a
size of 7.5 kb and a diameter of 27 nm. It has one serotype but multiple genotypes. Classic
findings of acute HAV infection include a mononuclear cell infiltrate, interface hepatitis, focal
hepatocyte dropout, ballooning degeneration, and acidophilic (Councilman-like) bodies. HAV
is present in the highest concentration in the feces of infected individuals; the greatest fecal
viral load tends to occur near the end of the HAV incubation period.

Viral Hepatitis. Hepatitis A virus as viewed through electron microscopy.

Most commonly, the virus spreads from person to person via the fecal-oral route.
Contaminated water and food, including shellfish collected from sewage-contaminated
water, have also resulted in epidemics of HAV infection. The virus may also be spread
through sexual (anal-oral) contact. [27] Transmission by blood transfusion is rare. Maternal-
neonatal transmission has not been established.

Although HAV infection occurs throughout the world, the risk is highest in developing
countries, areas of low socioeconomic status, and regions without sufficient sanitation.
Higher infection rates also exist in settings where fecal-oral spread is likely, such as daycare
centers. [28]

Other groups at high risk for HAV infection include international travelers, users of injection
and noninjection drugs, and men who have sex with men. [27] International travel is the most
frequently identified risk factor reported by case patients in the United States. [29] Close
contacts of infected individuals are also at risk. [27] The secondary infection rate for hepatitis
A virus in household contacts of patients with acute HAV infection is around 20%. Thus,
secondary infection plays a significant role in the maintenance of HAV outbreaks.
Hepatitis B
HBV, a member of the Hepadnaviridae family, is a 3.2-kb partially doubled-stranded DNA
virus. The positive strand is incomplete. The complete negative strand has four overlapping
genes, as follows:

Gene S codes for hepatitis B surface antigen (HBsAg), a viral surface polypeptide

Gene C codes for hepatitis B core antigen (HBcAg), the nucleocapsid protein; it also
codes for hepatitis B e antigen (HBeAg), whose function is unknown

Gene P codes for a DNA polymerase that has reverse transcriptase activity

Gene X codes for the X protein that has transcription-regulating activity

The viral core particle consists of a nucleocapsid, HBcAg, which surrounds HBV DNA, and
DNA polymerase. The nucleocapsid is coated with HBsAg. The intact HBV virion is known
as the Dane particle. Dane particles and spheres and tubules containing only HBsAg are
found in the blood of infected patients. In contrast, HBcAg is not detected in the circulation.
It can be identified by immunohistochemical staining of infected liver tissue.

HBV is known to have eight genotypic variants (genotypes A-H). Although preliminary
studies suggest that particular HBV genotypes may predict the virus’s response to therapy
or may be associated with more aggressive disease, it would be premature to incorporate
HBV genotype testing into clinical practice on a routine basis.

HBV is readily detected in serum, and it is seen at very low levels in semen, vaginal mucus,
saliva, and tears. The virus is not detected in urine, stool, or sweat. HBV can survive storage
at –20°C (–4°F) and heating at 60°C (140°F) for 4 hours. It is inactivated by heating at
100°C (212°F) for 10 minutes or by washing with sodium hypochlorite (bleach).

The major reservoir of HBV in the United States consists of the 850,000 to 2.2 million people
with chronic HBV infection. [26] In this group, those with HBeAg in their serum tend to have
higher viral titers and thus greater infectivity.

HBV is transmitted both parenterally and sexually, most often by mucous membrane
exposure or percutaneous exposure to infectious body fluids. Saliva, serum, and semen all
have been determined to be infectious. [26, 30] Percutaneous exposures leading to the
transmission of HBV include the transfusion of blood or blood products, injection drug use
with shared needles, hemodialysis, and needlesticks (or other wounds caused by sharp
implements) in healthcare workers. [26, 30]

Globally and in the United States, perinatal transmission is one of the major modes of HBV
transmission. The greatest risk of perinatal transmission occurs in infants of HBeAg-positive
women. By age 6 months, these children have a 70-90% risk of infection, and of those who
become infected, about 90% will go on to develop chronic infection with HBV. [9]

For infants born to HBeAg-negative women, the risk of infection is approximately 10-40%,
with a chronic infection rate of 40-70%. Even if transmission does not occur in the perinatal
period, these children are still at significant risk for the development of infection during early
childhood.

Groups at high risk for HBV infection include intravenous (IV) drug users, persons born in
endemic areas, and men who have sex with men. [26, 30] Others at risk include healthcare
workers exposed to infected blood or bodily fluids, recipients of multiple blood transfusions,
patients undergoing hemodialysis, heterosexual persons with multiple partners or a history
of sexually transmitted disease, institutionalized persons (eg, prisoners), and household
contacts or sexual partners of HBV carriers. [26, 30]

Hepatitis C
HCV, a member of the Flaviviridae family, is a 9.4-kb RNA virus with a diameter of 55 nm. It
has one serotype, but at least six major genotypes and more than 80 subtypes are
described, with as little as 55% genetic sequence homology. Genotype 1b is the genotype
most commonly seen in the United States, Europe, Japan, and Taiwan. Genotypes 1b and
1a (also common in the United States) are less responsive to interferon (IFN) therapy than
other HCV genotypes are. The wide genetic variability of HCV hampers the efforts of
scientists to design an effective anti-HCV vaccine.

HCV can be transmitted parenterally, perinatally, and sexually. Transmission occurs by

percutaneous exposure to infected blood and plasma. [18, 26] The virus is transmitted most
reliably through transfusion of infected blood or blood products, transplantation of organs
from infected donors, and the sharing of contaminated needles among IV drug users. [18, 26]
Transmission by sexual activity and household contact occurs less frequently. Perinatal
transmission occurs but is uncommon.

Genetic variations and HCV clearance

Genetic polymorphisms involving the IL28B gene have been found to affect the odds that
HCV can be cleared in a given patient. The IL28B gene encodes IFN lambda-3. A single
nucleotide polymorphism 3 kb upstream of the IL28B gene was associated with patients’
ability to clear HCV spontaneously.

In a study, about 53% of patients with the favorable C/C genotype and 23% of patients with
the less favorable T/T genotype spontaneously cleared the virus. [31] Of the patients who
were chronically infected with HCV, those with the C/C genotype were more likely to see
viral eradication after treatment with pegylated IFN (Peg-IFN) plus ribavirin. [32] In the same
study, the C/C genotype was more common in persons of European ancestry than in those
of African ancestry. In contrast, the T/T genotype was more common in persons of African
ancestry. [31] These observations may help to explain why black individuals typically exhibit
lower sustained virologic response (SVR) rates than white persons when treated with Peg-
IFN plus ribavirin.

Hepatitis D
HDV, the single species in the Deltavirus genus, is a 1.7-kb single-stranded RNA virus. The
viral particle is 36 nm in diameter and contains hepatitis D antigen (HDAg) and the RNA
strand. It uses HBsAg as its envelope protein; thus, HBV coinfection is necessary for the
packaging and release of HDV virions from infected hepatocytes.

Modes of transmission for HDV are similar to those for HBV. HDV is transmitted by exposure
to infected blood and blood products. It can be transmitted percutaneously and sexually. [33]
Perinatal transmission is rare.

Hepatitis E
HEV, the single species in the Hepevirus genus, is a 7.5-kb single-stranded RNA virus that
is 32-34 nm in diameter. It is transmitted primarily via the fecal-oral route, with fecally
contaminated water providing the most common means of transmission. [21, 34] Person-to-
person transmission is rare, though maternal-neonatal transmission does occur. [34]
Zoonotic spread is possible because some nonhuman primates (cows, pigs and wild boar,
sheep, goats, rodents, deer) are susceptible to the disease. [21, 35]

Other viruses
Hepatitis G virus (HGV) (also known as human pegivirus [HPgV]) is similar to viruses in the
Flaviviridae family, which includes HCV. [36] (It is an RNA virus within the Pegivirus A species
of the Flaviviridae family. [36] ) The HGV genome codes for 2900 amino acids. [34] The virus
has 95% homology (at the amino acid level) with hepatitis GB virus C (HGBV-C) and 26%
homology (at the amino acid level) with HCV.

Approximately 750 million people worldwide have HPgV viremia, with an estimated 1.5-2.5
billion people currently infected or with evidence of prior infection. [36] It can be transmitted
through blood and blood products. [34] HGV coinfection is observed in 6% of chronic HBV
infections and in 10% of chronic HCV infections. [34] About 75% of HPgV infections clear
within 2 years of infection, and 25% persist. [36] HGV is associated with acute and chronic
liver disease, but it has not been clearly implicated as an etiologic agent of hepatitis.

Other known viruses (eg, cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes simplex
virus [HSV], and varicella-zoster virus [VZV]) may also cause inflammation of the liver, but
they do not primarily target the liver.

Epidemiology
United States data
The Centers for Disease Control and Prevention (CDC) conducts national surveillance for
acute and chronic hepatitis infection. Data on chronic infections is limited because not all
states report this information: For the year 2014, the CDC received reports on chronic
hepatitis B virus (HBV) infection from 40 states and on chronic hepatitis C infection from 37
states. [9] Additionally, the numbers of reported cases for acute and chronic hepatitis
infection likely underestimate the true incidence of disease because most cases are
asymptomatic.

Beginning in 2011, the CDC incorporated a new method for estimating the number of cases
of hepatitis infection to better account for underreporting. [9] In 2014, there were 1239 cases
of hepatitis A virus (HAV) reported, [9] which was significantly less than the 2979 cases of
acute HAV infection reported in 2007. [1] Between 2011 and 2013, however, the number of
reported hepatitis A cases increased, including a large hepatitis A outbreak in 2013 due to
imported pomegranate seeds. [9, 29] After adjusting for underreporting and under
ascertainment, the CDC estimates that the actual number of new hepatitis A cases in 2014
was 2500. [9]

For HBV infection, rates of reported acute infections have been declining since 1990. [9]
There were 2791 cases of acute infection in 2014, [9] as compared to 4519 cases of acute
HBV infection reported in 2007. [1] With correction for asymptomatic cases and
underreporting, the true number of cases of acute hepatitis B infection in 2014 was
estimated at 18,100. [9] The incidence of childhood HBV infection is not well established,
because more than 90% of such infections in children are asymptomatic.

The CDC estimates that approximately 850,000 to 2.2 million people in the U.S are
chronically infected with HBV. [9, 26] Over 70% of these infections occurred in foreign-born
individuals, and over half of the chronic infections occurred in individuals identifying as
Asian/Pacific Islanders. [9]

The annual number of reported cases of acute hepatitis C increased steadily between 2010
and 2014. [9] There were 2194 case of acute hepatitis C infection reported in 2014; after
adjusting for underreporting, the CDC estimates that there were 30,500 new infections in
2014. [19] Approximately 2.7-3.9 million people In the United States have chronic hepatitis C.
[19]

International statistics
Globally, viral hepatitis was the seventh leading cause of death in 2013, up from the 10th
leading cause in 1990. [37] Worldwide, HAV is responsible for an estimated 1.4 million
infections annually. [38] About 2 billion people in the world have evidence of past or current
HBV infection, with 240 million chronic carriers of HBsAg. [5] HBV, along with the associated
infection by the hepatitis D virus, is one of the most common pathogens afflicting humans.
[39] HBV leads to 650,000 deaths annually as a result of viral hepatitis–induced liver

disease. [5]
The worldwide annual incidence of acute HCV infection is not easily estimated, because
patients are often asymptomatic. An estimated 71 million people are chronically infected
with HCV worldwide. [18] About 55-85% of these infected people progress to chronic HCV
infection, with a 15-30% risk of developing liver cirrhosis within two decades. [18] China, the
United States, and Russia have the largest populations of anti-HCV positive injection drug
users (IDUs). It is estimated that 6.4 million IDUs worldwide are positive for antibody to
hepatitis B core antigen (HBcAg) (anti-HBc), and 1.2 million are HBsAg-positive. [40]

Hepatitis A virus
HAV is transmitted most commonly via the fecal-oral route. Cases of transfusion-associated
HAV or illness caused by inoculation are uncommon.

HAV infection is common in the less-developed nations of Africa, Asia, and Central and
South America; the Middle East has a particularly high prevalence. Most patients in these
regions are infected when they are young children. Uninfected adult travelers who visit these
regions are at risk for infection.

Epidemics of HAV infection may be explained by person-to-person contact, such as occurs

at institutions, or by exposure to a common source, such as consumption of contaminated
water or food.

As sanitation has improved, the overall prevalence of hepatitis A in the United States and in
other parts of the developed world has decreased to less than 50% of the population.
Younger individuals in the United States are better protected from hepatitis A because of
guidelines adopted in 2006 recommending universal vaccination of children aged 1 year and
older. [9] Unfortunately, many older individuals in the United States still remain at risk.

Hepatitis B virus
Infection with HBV is defined by the presence of hepatitis B surface antigen (HBsAg).
Approximately 90-95% of neonates with acute HBV infection and 5% of adults with acute
infection develop chronic HBV infection. In the remaining patients, the infection clears, and
these patients develop a lifelong immunity against repeated infections.

Of the approximately 5% of the world’s population (ie, 350 million people) that is chronically
infected with HBV, about 20% will eventually develop HBV-related cirrhosis or hepatocellular
carcinoma (HCC). According to the World Health Organization (WHO), HBV is the 10th
leading cause of death worldwide. [41]

More than 10% of people living in sub-Saharan Africa and in East Asia are infected with
HBV. Maintenance of a high HBsAg carriage rate in these parts of the world is partially
explained by the high prevalence of perinatal transmission and by the low rate of HBV
clearance by neonates.

In the United States, about 250-350 patients die of HBV-associated fulminant hepatic failure
(FHF) each year. A pool of approximately 1.25 million chronic HBV carriers exists in the
United States. Of these patients, 4000 die of HBV-induced cirrhosis each year, and 1000 die
of HBV-induced HCC.

Perinatal transmission

The vast majority of HBV cases around the world result from perinatal transmission.
Infection appears to occur during the intrapartum period or, rarely, in utero. Neonates
infected via perinatal infection are usually asymptomatic. Although breast milk can contain
HBV virions, the role of breastfeeding in transmission is unclear.

Sexual transmission

HBV is transmitted more easily than human immunodeficiency virus (HIV) or HCV. Infection
is associated with vaginal intercourse, genital-rectal intercourse, and oral-genital
intercourse. An estimated 30% of sexual partners of patients infected with HBV also contract
HBV infection. However, HBV cannot be transmitted through kissing, hugging, or household
contact (eg, sharing towels, eating utensils, or food). Sexual activity is estimated to account
for as many as 50% of HBV cases in the US.

Parenteral transmission

HBV was once a common cause of posttransfusion hepatitis. Screening of US blood donors
for anti-HBc, beginning in the early 1970s, dramatically reduced the rate of HBV infection
associated with blood transfusion. According to the National Heart, Lung and Blood Institute,
the risk that a blood donation is infected with hepatitis B is 1 in 205,000. [42]

Patients with hemophilia, those on renal dialysis, and those who have undergone organ
transplantation remain at increased risk of HBV infection. IDU accounts for 20% of US cases
of HBV. A history of HBV exposure is identified in approximately 50% of IDUs. The risk of
acquiring HBV after a needle stick from an infected patient is estimated to be as high as 5%.

Healthcare associated

Hepatitis B outbreaks have been associated with healthcare settings. Between 2008 and
2015, there were 23 outbreaks and 175 outbreak-associated cases of hepatitis B associated
with healthcare settings reported in the United States. [43] Outbreaks were reported in long-
term care facilities and outpatient clinic settings. The CDC noted that these numbers likely
underestimate the true incidence of healthcare-associated outbreaks because of the
asymptomatic course of hepatitis B infection as well as the long incubation period.
Additionally, there is no requirement to report these cases to the CDC if they have been
investigated by state and local health authorities. [43]

Sporadic cases

In approximately 27% of cases, the cause of HBV infection is unknown. Some of these
cases, in fact, may be due to sexual transmission or contact with blood.
Hepatitis C virus
HCV is the most frequent cause of parenteral non-A, non-B (NANB) hepatitis worldwide.
Hepatitis C is prevalent in 0.5-2% of populations in nations around the world. The highest
rates of disease prevalence are found in patients with hemophilia and in IDUs.

In the 1980s, as many as 180,000 new cases of HCV infection were described each year in
the United States; by 1995, there were only 28,000 new cases each year. [44] The
decreasing incidence of HCV was explained by a decline in the number of cases of
transfusion-associated hepatitis (because of improved screening of blood products) and by
a decline in the number of cases associated with IDU. New cases of hepatitis C infection
tend to occur in individuals who are young and white, with a history of IDU and opioid use. [9]

Transmission via blood transfusion

Screening of the US blood supply has dramatically reduced the incidence of transfusion-
associated HCV infection. [19, 45] Before 1990, 37-58% of cases of acute HCV infection (then
known as NANB) were attributed to the transfusion of contaminated blood products; at
present, only about 4% of acute cases are attributed to transfusions. The risk of having a
blood donation infected with hepatitis C is 1 in 2 million. [42] Acute hepatitis C remains an
important issue in dialysis units, where patients’ risk for HCV infection is about 0.15% per
year.

Transmission via intravenous and intranasal drug use

IDU remains an important mode of transmitting HCV. The use of intravenous (IV) drugs and
the sharing of paraphernalia used in the intranasal snorting of cocaine and heroin account
for approximately 60% of new cases of HCV infection. More than 90% of patients with a
history of IDU have been exposed to HCV.

Transmission via occupational exposure

Occupational exposure to HCV accounts for approximately 4% of new infections. On

average, the chance of acquiring HCV after a needle-stick injury involving an infected
patient is 1.8% (range, 0-7%). Reports of HCV transmission from healthcare workers to
patients are extremely uncommon.

Sexual transmission

Approximately 20% of cases of hepatitis C appear to be due to sexual contact. In contrast to

hepatitis B, approximately 5% of the sexual partners of those infected with HCV contract
hepatitis C.

The US Public Health Service (USPHS) recommends that persons infected with HCV be
informed of the potential for sexual transmission. Sexual partners should be tested for the
presence of antibodies to HCV (anti-HCV). Safe-sex precautions are recommended for
patients with multiple sex partners. Current guidelines do not recommend the use of barrier
precautions for patients with a steady sexual partner. However, patients should avoid
sharing razors and toothbrushes with others. In addition, contact with patients’ blood should
be avoided.

Perinatal transmission

Perinatal transmission of HCV occurs in 5.8% of infants born to mothers infected with HCV.
[46] The risk of perinatal transmission of HCV is higher (about 18%) in children born to

mothers coinfected with human immunodeficiency virus (HIV) and HCV. [47] Between 2011
and 2014, the proportion of infants born to HCV-infected mothers increased by 68%
nationally, indicating an increase in the number of infants who are at risk for vertical
transmission of HCV. [46]

Healthcare associated

Hepatitis C outbreaks have been associated with healthcare settings. Between 2008 and
2015, there were 33 outbreaks and 239 outbreak-associated cases of hepatitis C related to
US healthcare settings. [43] Outbreaks occurred in outpatient facilities and hemodialysis
settings. [43] The CDC noted that these numbers likely underestimate the true incidence of
healthcare-associated outbreaks because of the asymptomatic course of hepatitis C
infection and its long incubation period. Additionally, there is no requirement to report these
cases to the CDC if they have been investigated by the state and local health authorities. [43]

Hepatitis D virus
HDV requires the presence of HBV to replicate; thus, HDV infection develops only in
patients who are positive for HBsAg. [48] Patients may acquire HDV as a coinfection (at the
same time that they contract HBV), or the HDV may superinfect patients who are chronic
HBV carriers. Hepatitis D is not a reportable disease in the United States, thus, accurate
data regarding HDV infections are scarce. However, it is estimated that approximately 4-8%
of cases of acute hepatitis B involve coinfection with HDV. [49, 50, 51]

HDV is believed to infect approximately 5% of the world’s HBsAg carriers (ie, about 15
million with chronic HBV/HDV). [5, 33] The prevalence of HDV infection in South America and
Africa is high. Italy and Greece are well-studied areas of intermediate endemicity. Only
about 1% of HBV-infected individuals in the United States and Northern Europe are
coinfected with HDV.

The sharing of contaminated needles in IDU is thought to be the most common means of
transmitting HDV. IDUs who are also positive for HBsAg have been found to have HDV
prevalence rates ranging from 17% to 90%. Sexual transmission and perinatal transmission
are also described. The prevalence of HDV in sex workers in Greece and Taiwan is high.

Hepatitis E virus
HEV is the primary cause of enterally transmitted NANB hepatitis. It is transmitted via the
fecal-oral route and appears to be endemic in some parts of less-developed countries,
where most outbreaks occur. HEV can also be transmitted vertically to the babies of HEV-
infected mothers. It is associated with a high neonatal mortality. [52]

In one report, anti-HEV antibodies were found to be present in 29% of urban children and
24% of rural children in northern India. [53] Sporadic infections are observed in persons
traveling from Western countries to these regions.

Prognosis
The prognosis of viral hepatitis varies, depending on the causative virus.

Hepatitis A virus (HAV) infection usually is mild and self-limited, and infection confers lifelong
immunity against the virus. Overall mortality is approximately 0.02% [9] ; in general, children
younger than 5 years and adults older than 50 years have the highest case-fatality rates.
Older patients are at a greater risk for severe disease: Whereas icteric disease occurs in
fewer than 10% of children younger than 6 years, it occurs in 40-50% of older children and
in 70-80% of adults with HAV. Three rare complications are relapsing hepatitis, cholestatic
hepatitis, and fulminant hepatic failure (FHF).

The risk of chronic HBV infection in infected older children and adults approaches 5-10%.
Patients with such infection are at risk for cirrhosis and hepatocellular (HCC). FHF develops
in 0.5-1% of patients infected with HBV; the case-fatality rate in these patients is 80%.
Chronic HBV infection is responsible for approximately 5000 deaths per year from chronic
liver disease in the United States.

Chronic infection develops in 50-60% of patients with hepatitis C. Chronically infected

patients are at risk for chronic active hepatitis, cirrhosis, and HCC. In the United States,
chronic HCV infection is the leading indication for liver transplantation. [19] In 2014, the
number of HCV-related deaths rose to 19,659 from 15,106 in 2007, with over 50% occurring
in people aged 55-64 years. [9]

Patients with chronic HBV infection who are coinfected with HDV also tend to develop
chronic HDV infection. Chronic coinfection with HBV/HDV often leads to rapidly progressive
subacute or chronic hepatitis, with as many as 70-80% of these patients eventually
developing cirrhosis.

HEV infection is usually mild and self-limited. The case-fatality rate reaches 15-20% in
pregnant women. HEV infection does not result in chronic disease.

Complications
In general, complications of viral hepatitis may include the following:
 Acute or subacute hepatic necrosis

Chronic active hepatitis

Chronic hepatitis

Cirrhosis

Hepatic failure

Hepatocellular carcinoma (HCC) in patients with HBV or HCV infection

Hepatitis B

One of the major complications of hepatitis B is the development of chronic infection. An

estimated 240 million people worldwide are chronically infected with HBV. [5] In the United
States, 850,000 to 2.2 million people are estimated to have chronic HBV infection. [26]
Patients with such infection are at risk for the subsequent development of chronic active
hepatitis, cirrhosis of the liver, and eventual HCC. Each year, approximately 650,000 deaths
occur worldwide as a result of chronic HBV infection. [5]

Patients infected at an early age are at greatest risk for chronic HBV infection: Whereas
90% of those infected at birth and 30-50% of children infected at age 1-5 years develop
chronic HBV infection, only 5% of older children or adults go on to develop chronic infection.
[9] The risk of chronic infection is also higher in patients who are immunocompromised.

Patients with chronic HBV infection are at significantly higher risk for HCC. In fact, HCC is
the leading cause of cancer-related deaths in areas where HBV is endemic. Globally, HBV is
responsible for 45% of the world’s primary liver cancers. [5] Cancer in this setting is
postulated to result from repeated bouts of chronic inflammation and cellular regeneration.
HCC develops an average of 25-30 years after the initial infection.

Another major complication of HBV infection is the development of FHF. In approximately

0.5-1% of HBV-infected patients, the disease progresses to FHF, with coagulopathy,
encephalopathy, and cerebral edema. The case-fatality rate for these patients approaches
80%. [2]

Hepatitis C

Acute infection with HCV may rarely cause FHF. [54] Approximately 75-85% of patients with
hepatitis C become chronically infected. [19] About 60-70% of patients will have ongoing
chronic liver disease with laboratory evidence of fluctuating or persistently elevated liver
enzymes. Of those with chronic infection, 5-20% may go on to develop cirrhosis. The
progression from initial infection to the development of cirrhosis may take 20-30 years. [19]

Cirrhosis related to chronic HCV infection is also strongly linked to the development of HCC,
which usually develops after 30 years in patients who are chronically infected. Of patients
with HCV-associated cirrhosis, 20-25% may progress to liver failure and death. [54] As noted
earlier, in the United States, cirrhosis associated with chronic hepatitis C is a leading
indication for liver transplantation. [19]

Extrahepatic complications of hepatitis C

Patients with chronic hepatitis C are also at risk for extrahepatic complications. In essential
mixed cryoglobulinemia, HCV may form immune complexes with anti-HCV immunoglobulin
G (IgG) and with rheumatoid factor (RF). The deposition of immune complexes may cause
small-vessel damage. Complications of cryoglobulinemia include rash, vasculitis, and
glomerulonephritis.

Other extrahepatic complications of HCV infection include focal lymphocytic sialadenitis,

autoimmune thyroiditis, porphyria cutanea tarda, lichen planus, and Mooren corneal ulcer.
Some cases of non-Hodgkin lymphoma can be attributed to HCV infection.

Patient Education
Refer patients with infectious hepatitis to their primary care providers for further counseling
specific to their disease; the precise etiologic virus is unlikely to be known at the time of
discharge from the emergency department.

Counsel patients regarding the importance of follow-up care to monitor for evidence of
disease progression or development of complications. Remind them to exercise meticulous
personal hygiene, including thorough hand washing. Instruct them not to share any articles
that have the potential for contamination with blood, semen, or saliva, including needles,
toothbrushes, or razors.

Inform food handlers suspected of having hepatitis A that they should not return to work until
their primary care physician can confirm that they are no longer shedding the virus. Instruct
patients to refrain from using any hepatotoxins, including ethanol and acetaminophen.

Clinical Presentation
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