7: Viral Hepatitis

CHAPTER 7
Viral Hepatitis


Emily Jeanne Cartwright and Yun F. (Wayne) Wang


Emory University School of Medicine, Atlanta, GA, USA


7.1 Introduction/background


Hepatitis means inflammation of the liver; it can be caused by infections, toxins, or other systemic conditions. While many viruses (including cytomegalovirus (CMV), Epstein–Barr virus ([EBV), adenovirus, yellow fever virus, and others) can cause hepatitis, this chapter will focus on the viruses that cause hepatitis as the primary clinical manifestation; namely, hepatitis A, B, C, D and E. Patients with acute viral hepatitis usually develop nausea, anorexia, malaise, and abdominal pain. Patients often develop fever, jaundice, dark urine, and clay-colored stools. Laboratory studies demonstrate elevated aminotransferase levels. Occasionally, extrahepatic manifestations including rash, arthralgias, arthritis, cryoglobulinemia, and glomerulonephritis occur. Diagnostic studies include serology, antigen detection, nucleic acid quantitation, genotyping, and sequencing, and they vary for each hepatitis virus.


Epidemics of jaundice have been described as far back as the 1600s. It was noted during treatment for smallpox in 1885 that clinics with poor infection control practices, including syringe reuse, had more outbreaks of hepatitis. Work done by Krugman et al. in the 1950s established two distinct clinical entities of hepatitis, one with fecal–oral transmission and the other with parenteral transmission; his work also established the incubation period of both viruses [44]. In 1965, the hepatitis B surface antigen was isolated [14]. In 1973, routine screening of blood donors for hepatitis B was started. In 1977, hepatitis D virus was isolated. In 1979, hepatitis A virus was grown in tissue culture. In 1980, hepatitis E was discovered. Hepatitis C was isolated and blood supply screening initiated in 1991 [3].


In 2012, an estimated 4.4 million Americans were living with chronic hepatitis and many do not know they are infected. Additionally, viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation [15,39]. The epidemiological, diagnostic considerations, and commercial laboratory methods used in the management of viral hepatitis will be discussed in this chapter; however, histological techniques used to diagnose and stage viral hepatitis are beyond the scope of this chapter.


7.2 Clinical manifestations, epidemiology, and diagnostic considerations by virus


7.2.1 Hepatitis A virus


Hepatitis A virus (HAV) is a nonenveloped, single-stranded RNA virus in the Picornaviridae family (Table 7.1). Infection with HAV generally causes an acute, self-limited, inflammatory disease of the liver. The spectrum of clinical disease ranges from asymptomatic infection to, rarely, fulminant disease. Patients with HAV infection usually describe a mild prodrome of fevers, chills, headache, malaise and fatigue followed (usually within 1–7 days) by jaundice, dark urine, and pale or clay-colored feces [41]. One study found that 66% of patients had recovered from acute infection with hepatitis A within 2 months, 85% within 3 months, and nearly all recovered by 6 months [68]. Infection with HAV does not cause chronic liver disease, but disease relapse has been reported in some cases [63,68]. Clinical manifestations vary by age, with older persons having more symptoms (e.g., jaundice) while children less than 6 years of age are usually asymptomatic [32,76]. According to the Centers for Disease Control and Prevention (CDC), the mortality rate from HAV infection in the United States was 0.12 deaths per 100,000 population in 2008 [17].


Table 7.1 Summary of hepatitis A, B, C, D, E viruses



































































Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Virus family Picornaviridae Hepadnaviridae Flaviviridae Deltaviridae Hepeviridae
Nucleic acid Single-strand RNA Partially double-strand DNA Single-strand RNA Single-strand RNA, lacks RNA polymerase Single-strand RNA
Envelope No Yes Yes Yes No
Incubation period,
median
32 days [44] 65 days [44] 14–160 days 2–8 weeks 15–45 days
Modes of transmission Fecal–oral, person-to-person Blood, sexual, perinatal Blood, sexual (rare) Blood, sexual Fecal–oral, waterborne
Risk factors Travel to endemic areas, MSM, food-/waterborne outbreaks, daycare settings MSM, IVDU, blood transfusion IVDU, blood transfusion Requires coinfection with hepatitis B Contaminated water, zoonotic exposure, pregnancy
Chronic infection No Yes Yes Requires coinfection with hepatitis B Can occur
Vaccine preventable Yes Yes No Via hepatitis B vaccine Vaccine under development

The number of reported cases of HAV infections has been decreasing each year in the United States since the vaccine was first introduced in 1996. In 2006, the Advisory Committee on Immunization Practices (ACIP) recommended the hepatitis A vaccine routinely to all children in the United States [24]. In 2010, 1670 cases of HAV infection were reported in the United States, which represents a significant decrease from 13,397 cases in 2000 [17]. Worldwide, seroprevalence is classified into regions of high, intermediate, low, or very low HAV endemicity (Figure 7.1).

World map with markings—four differently shaded parts for high, intermediate, low, and very low—for estimated hepatitis A virus prevalence.

Figure 7.1 Hepatitis A seroprevalence worldwide.


(Source: wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-a.htm)


HAV is transmitted through the fecal–oral route. Transmission occurs through food and waterborne outbreaks and close personal contact with infected individuals. Reported risk factors for HAV acquisition include international travel, close contact with an infected person, employee or child in a daycare center, food or water exposure during a common-source outbreak, illicit drug use, and men who have sex with men [40]. Fecal excretion of HAV can occur 14–21 days before the onset of jaundice and can continue until 8 days after symptom onset (Figure 7.2). Prolonged fecal shedding of HAV can occur, especially in infants and children; HAV RNA has been detected in the feces of infants up to 4 months after infection [59].

Graph of the clinical, virologic, and serologic course of acute hepatitis A virus (HAV) infection displaying two curves for IgG anti-HAV and IgM anti-HAV.

Figure 7.2 The clinical, virologic, and serologic course of acute hepatitis A virus (HAV) infection. ALT, alanine aminotransferase.


(Reproduced with permission from Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 7th Edition, 2010, M.P. Curry and S. Chopra, Acute Viral Hepatitis, 1577–1592, Churchill Livingstone/Elsevier, Philadelphia, PA.)


Acute HAV infection is diagnosed through detection of immunoglobulin M (IgM) antibody to hepatitis A virus. IgM anti-HAV is detectable 5–10 days after exposure (Figure 7.2). Past exposure can be identified by detection of immunoglobulin G (IgG) to HAV. HAV RNA can be detected in serum and stools of most persons during the acute phase of infection using nucleic acid amplification but this test is generally only used in research settings. Detection of HAV antigen in the stool (by enzyme immunoassay or HAV RNA PCR) does not necessarily indicate active infection; the period of infectivity is shorter than the period during which HAV RNA is detectable in feces.


Treatment is generally supportive during acute HAV infection. Post-exposure prophylaxis with the HAV vaccine and, in some instances, immunoglobulin, of exposed, susceptible contacts is recommended [5].


7.2.2 Hepatitis B virus


Hepatitis B virus (HBV) is a partially double stranded, enveloped, DNA virus in the Hepadnavirus family (Table 7.1); HBV is currently classified into eight main genotypes (named A–H). The onset of acute HBV infection is generally insidious, with anorexia, nausea, vomiting, abdominal distension, and absent to mild fever; arthralgias and rash may occur. Disease severity ranges from an asymptomatic transaminitis to fulminant hepatic necrosis (occurs in < 1%). The incubation period is 65 days (range: 28–160 days) [44]. The case-fatality rate is 1% but may be higher in older adults, pregnant women, and newborns. The risk of developing a chronic HBV infection decreases with increasing age at time of infection. Chronic infection occurs in > 90% of perinatally infected infants, 10–20% of children infected between ages 1 and 5 years, and approximately 5% of immunocompetent older children and adults [43]. Over time, 15–40% of persons with chronic HBV infection will develop liver cirrhosis or hepatocellular carcinoma [20].


In 2010, 3350 cases of acute hepatitis B were reported to the CDC [17]. There are an estimated 800,000 to 1.4 million people living with chronic hepatitis B infection in the United States [75]. Globally, an estimated 240 million are chronically infected with hepatitis B and an estimated 600,000 persons worldwide die from hepatitis B-related liver disease annually [52] (Figure 7.3). The incidence of acute hepatitis B in the United States has declined dramatically over the past two decades with universal vaccination recommendations (from 11.5 acute cases per 100,000 population in 1985 to 1.1 per 100,000 in 2010) [17].

World map with markings—three differently shaded parts for high ≥8%, intermediate 2%–7%, and low <2%—for prevalence of hepatitis B surface antigen.

Figure 7.3 Hepatitis B seroprevalence worldwide.


(Source: wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-b.htm)


HBV is transmitted by percutaneous or mucosal exposure to blood or body fluids of an infected person, most often through injection drug use, sexual contact, from mother to child (perinatal transmission), or from unsafe blood transfusions. HBV is 50–100 times more infectious than HIV and can survive outside the body for at least 7 days [16].


The detection of hepatitis B surface antigen (HBsAg) indicates either acute or chronic active infection (Figure 7.4). The presence of IgM antibody to the hepatitis B core antigen (IgM anti-HBc) indicates acute infection (within past 6 months), while the IgG anti-HBc is nonspecific and can occur in acute, chronic, or resolved infection (Figure 7.4, Table 7.2). Antibody to HBV surface antigen (anti-HBs) develops after natural or vaccine exposure and generally indicates recovery and immunity from HBV infection. Hepatitis B E-antigen (HBeAg) is found during acute and chronic hepatitis B infection. The presence of HBeAg indicates that the virus is replicating and there is increased infectivity. Hepatitis B E antibody (anti-HBe) is a predictor of long-term clearance of HBV in patients on antiviral therapy (Figure 7.4). The US Preventative Services Task Force (PSTF) recommends performing an HBsAg test on all pregnant women at the first prenatal visit.

Graph of the clinical, virologic, and serologic course of acute hepatitis B virus (HBV) infection displaying four curves for HBsAg, IgM anti-HBc, total anti-HBc, and anti-HBs.

Figure 7.4 The clinical, virologic, and serologic course of acute hepatitis B virus (HBV) infection. ALT, alanine aminotransferase; HBc, hepatitis B core; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; IgG, immunoglobulin G; IgM, immunoglobulin M.


(Reproduced with permission from Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 7th Edition, 2010, M.P. Curry and S. Chopra, Acute Viral Hepatitis, 1577–1592, Churchill Livingstone/Elsevier, Philadelphia, PA.)


Table 7.2 Interpretation of hepatitis B diagnostic studies












































Susceptible,
Never exposed
Immune through natural exposure Immune through vaccination Acute infection Chronic Infection Indeterminate*
HBsAg + +
IgG Anti-HBc + + + +
IgM Anti-HBc +
Anti-HBs + +

* Could indicate one of four scenarios including: (i) resolved infection, (ii) false positive anti-HBC, (iii) chronic infection at low level, and (iv) resolving acute infection.


Treatment of chronic active HBV infection is indicated in some patients. The US Food and Drug Administration (FDA) approved therapies for hepatitis B, as of this writing, include interferon, lamivudine, adefovir, entecavir, tenofovir, and telbuvidine [45].


HBV vaccine is recommended for all infants in the United States [47] and throughout the world [51]. The complete vaccine series induces protective antibody levels in more than 95% of infants, children, and young adults. Protection lasts at least 20 years and is possibly lifelong [47].


7.2.3 Hepatitis D virus


Hepatitis D virus (HDV), also known as “delta hepatitis,” is a unique RNA virus that can only infect and replicate in cells in the presence of HBV (Table 7.1). HDV, therefore, is acquired through either HBV–HDV coinfection or by HDV superinfection [57]. Persons who are coinfected with hepatitis D may have more severe hepatic inflammation compared to HBV mono-infected persons [10].


Worldwide, approximately 15 million people are infected with HDV with higher prevalence in Venezuela, Brazil, Romania, and Italy and lower prevalence in the United States [58]. Both IgM and IgG antibodies to the hepatitis delta antigen (anti-HDV) are detectable during infection. HDV nucleic acid detection is available in research settings. Interferon alfa-2a is the only FDA-approved treatment for chronic hepatitis D, as of this writing. Vaccination against hepatitis B infection is an important tool to prevent HDV infection.


7.2.4 Hepatitis C virus


Hepatitis C virus (HCV) is an enveloped, single-strand RNA virus in the Flaviviridae family (Table 7.1). HCV infection is the most common chronic bloodborne infection in the United States; approximately 3.2 million Americans are chronically infected [11]. Worldwide, an estimated 170 million persons have chronic HCV infection [1] (Figure 7.5). Six HCV genotypes (named 1–6) are known to exist with variable geographic distribution. Genotype 1 is most common in the United States, while genotype 4 is seen most frequently in Egypt [55]. Most acute HCV infections are asymptomatic, with less than 20% of persons developing jaundice. Chronic HCV infection develops in 70–85% of HCV-infected persons; 60–70% of chronically infected persons have intermittently elevated liver transaminase levels [8,34,70]. Chronically infected persons serve as a source of transmission to others and are at risk for cirrhosis, hepatocellular carcinoma, or other extrahepatic manifestations of HCV, even decades after infection.

World map with markings—five differently shaded parts for >2.9%, 2.0%–2.9%, 1.0%–1.9%, <1.0% and no data—for prevalence of hepatitis C virus infection.

Figure 7.5 Hepatitis C seroprevalence worldwide.


(Source: wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm)


HCV is most efficiently transmitted through large or repeated percutaneous exposure to infected blood. Although much less frequent, occupational, perinatal, and sexual exposures can result in the transmission of HCV. Since implementation of routine blood donor screening in 1992, transmission of HCV via blood products is now extremely rare in the developed world. The use of contaminated needles for injection drug use is currently the most common method of HCV transmission in the United States [6]. However, healthcare settings are increasingly recognized as potential sources for HCV transmission, specifically through hemodialysis, unsafe injection practices, reuse of needles and fingerstick devices, and other lapses in infection control practices [2,25,30,48,67].


Detection of antibody to HCV can indicate past exposure to HCV with viral clearance, chronic active infection, or, rarely, a falsely positive test (Figure 7.6). Previously, recombinant immunblot assays were recommended to distinguish viral clearance from a false-positive HCV antibody result, however, this assay is no longer commercially available [7]. HCV RNA PCR assay is now recommended to distinguish past from current HCV infection [4]. Routine prenatal HCV screening is not recommended, however, antibody screening is appropriate for women with risk factors for infection.

Flowchart of testing sequence for identifying current hepatitis C virus (HCV) infection from HCV antibody to stop (if no HCV antibody detected), link to care, and additional testing as appropriate.

Figure 7.6 HCV. The recommended testing sequence for identifying current hepatitis C virus (HCV) infection.


(Source: www.cdc.gov/mmwr/pdf/wk/mm62e0507a2.pdf)


While no HCV vaccine exists, the infection can be cleared in some patients with antiviral therapies. Pegylated interferon (PegIFN) combined with ribavirin (RBV) was the standard treatment for many years but newer, direct-acting antiviral (DAA) drugs are now recommended and have been shown to increase the likelihood of achieving a sustained virologic response [27].


A sustained virologic response (SVR) is defined as undetectable HCV RNA 3 to 6 months after completing antiviral treatment (considered a virologic “cure”). Three categories describe patients who underwent antiviral treatment for HCV but failed to achieve SVR: null responders (HCV RNA did not decline by at least 2 log IU/mL at treatment week 12), partial responders (HCV RNA decline by 2 log IU/mL by week 12 but HCV RNA was still detectable at treatment week 24), and relapsers (HCV RNA was undetectable but then reappeared after treatment ended). The impact of antiviral resistance-associated variants (RAV) on treatment outcomes is an area of active study. Testing for the presence of RAVs either at baseline or in patients who have experienced a treatment failure is a practice that is currently evolving.


The current guidelines for the treatment of Hepatitis C emphasize both the need for a genotype determination prior to treatment decisions as well as precise HCV RNA determinations throughout treatment regimens.


7.2.5 Hepatitis E virus


Hepatitis E virus (HEV) is a single-strand RNA, nonenveloped virus in the Hepeviridae family (Table 7.1). HEV appears to be transmitted through the ingestion of fecal matter, even in microscopic amounts. HEV infection manifests in two clinically and epidemiologically distinct forms of diseases [66]. One form causes waterborne outbreaks in developing countries, with acute onset of disease, and is associated with genotypes 1 and 2. Such large HEV outbreaks have been reported from India [49], China [13], Mexico [69], Sudan [28], and Uganda [65] (Figure 7.7). The second form, often associated with genotypes 3 and 4, causes a mild clinical presentation often with extrahepatic manifestations in developed countries. Transmission of this second form of hepatitis E may be from foodborne and zoonotic exposures, specifically swine. HEV genotype 3 has been detected in pork meant for human consumption in several countries [33,62].

World map with markings—three differently shaded parts for highly endemic, endemic, and not endemic or endemicity unknown—for levels of endemicity for hepatitis E virus.

Figure 7.7 Hepatitis E seroprevalence worldwide.


(Source: wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-e.htm)

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Dec 10, 2017 | Posted by in MICROBIOLOGY | Comments Off on 7: Viral Hepatitis
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