Acute viral hepatitis

Chapter 3 Acute viral hepatitis



Raymond S. Koff, MD



Key Points



1 Viral hepatitis is the most common cause of liver disease in the world; acute infections with their sequelae are responsible for 1 to 2 million deaths annually.

2 The nonenveloped, enterically transmitted hepatitis viruses (HAV and HEV), in general, are self-limited infections, but severe hepatitis may develop in some cases; rarely, chronic hepatitis E has been reported in organ-transplant recipients. The blood-borne hepatitis viruses (HBV, HDV, and HCV) are enveloped agents frequently associated with persistent infection, prolonged viremia, and the development of chronic liver disease and its sequelae.

3 A wide spectrum of clinical illness is well documented, ranging from asymptomatic, anicteric infection to acute liver failure (fulminant hepatitis); with the exception of acute hepatitis C, no specific or effective treatment of acute viral hepatitis is available; liver transplantation is indicated in acute liver failure when recovery seems unlikely.

4 Highly effective and safe vaccines are available for preexposure immunoprophylaxis of HAV and HBV infection; for postexposure immunoprophylaxis of HAV, HAV vaccine is preferred but immune globulin may be used, whereas for postexposure immunoprophylaxis of HBV, both hepatitis B immune globulin (HBIG) and HBV vaccine are used.

5 Immune globulin preparations are not available for the prevention of HEV or HCV infection. No vaccine for the prevention of HCV infection exists. An effective HEV vaccine is not yet commercially available but remains in development. HBV vaccination prevents HDV infection, but for persons with established HBV infection, vaccines to prevent HDV superinfection are not available.


Importance



1. Viral hepatitis is the most common cause of liver disease worldwide.

2. As many as 7% of the global population is chronically infected by the hepatitis B virus (HBV), and 3% are infected by the hepatitis C virus (HCV).

3. Many episodes of hepatitis are anicteric, inapparent, subclinical, and unrecognized.

4. Other episodes of hepatitis are severe and may result in acute liver failure.

5. Globally, viral hepatitis is the major cause of persistent viremia.

6. The sequelae of chronic infection include cirrhosis, end-stage liver disease, hepatocellular carcinoma, and premature death.

7. With its sequelae, viral hepatitis is responsible for 1 to 2 million deaths annually.


Agents


The agents of acute viral hepatitis can be broadly classified into two groups: the enterically transmitted agents and the blood-borne agents.



Enterically transmitted agents


These agents, namely, hepatitis A virus (HAV) and hepatitis E virus (HEV)


image are nonenveloped viruses

image survive intact when exposed to bile/detergents

image are shed in feces

image do not result in a prolonged viremic or intestinal carrier state

image only HEV has been linked rarely to chronic liver disease.

image A third enterically transmitted hepatitis virus may exist, is transmissible to chimpanzees,

image replicates in the liver, and induces immune responses but remains unidentified.


1. HAV
a. Classified as a picornavirus, subclassified as a hepatovirus

b. 27 to 28 nm in diameter with cubic symmetry

c. Single-stranded, linear RNA molecule, 7.4 kb in one open reading frame

d. One serotype in human beings; three or more genotypes

e. Containing a single immunodominant neutralization site

f. Containing four major virion polypeptides in capsomere

g. Replication in cytoplasm of infected hepatocyte through RNA-dependent RNA polymerase; no definitive evidence of replication in intestine

h. High degree of chemical and thermal resistance to inactivation

i. Propagated in nonhuman primate and human cell lines

2. HEV
a. Classified with Hepeviridae, subclassified as a hepevirus

b. 27 to 34 nm in diameter

c. Linear RNA molecule, 7.2 to 7.4 kb

d. RNA genome with three overlapping open reading frames encoding structural proteins and nonstructural proteins involved in HEV replication:
image RNA-dependent RNA polymerase (RNA replicase)

image Helicase

image Cysteine protease

image Methyltransferase

e. Only one serotype identified in human beings; four major genotypes

f. Immunodominant neutralization site on structural protein encoded by second open reading frame

g. Can be propagated in transfected human hepatocellular carcinoma cell lines and in human embryo lung diploid cells

3. Other enterically transmitted agents
image Occasional outbreaks of other enterically transmitted hepatitis, without serologic markers of HAV or HEV; infection appears transmissible to chimpanzees, with replication in liver


Blood-borne agents


These agents, namely, HBV, hepatitis D virus (HDV), and HCV, are


image enveloped viruses

image disrupted by exposure to bile/detergents

image not shed in feces

image linked to chronic liver disease

image associated with persistent viremia


1. HBV
a. Human-infecting member of hepatotropic DNA-containing viruses, the Hepadnaviridae

b. Eight genotypes (A through H): genotype C appears to be associated with more severe chronic disease, and genotype D is less responsive to interferon-based therapy

c. 42-nm spherical particle with
image A 27-nm diameter, electron-dense, nucleocapsid core

image A 7-nm thick outer lipoprotein envelope

d. HBV core containing circular, partially double-stranded DNA (3.2 kb in length) and
image DNA polymerase protein with reverse transcriptase activity

image Hepatitis B core antigen (HBcAg), a structural protein of the nucleocapsid

image Hepatitis B e antigen (HBeAg), a nonstructural, secretory protein that correlates imperfectly with active HBV replication

image Hepatitis B x protein, a transcriptional activator, linked to hepatocarcinogenesis.

e. HBV outer lipoprotein envelope containing
image Hepatitis B surface antigen (HBsAg), with three envelope proteins: major, large, and middle proteins

image Minor lipid and carbohydrate components

image HBsAg present in 22-nm spherical or tubular noninfectious particles, in excess of intact HBV particles

f. One major serotype; many subtypes based on HBsAg protein diversity

g. HBV mutant viruses as a consequence of poor proofreading ability of reverse transcriptase or emergence of resistance; examples:
image HBeAg-negative precore or core promoter mutant

image HBV vaccine-induced escape mutant (rare)

image Nucleos(t)ide-induced resistant mutant

h. Replication occurring through reverse transcription of pregenomic RNA

i. Liver major but not only site of HBV replication

j. Limited replication in vitro in primary adult and fetal human hepatocytes

2. HDV
a. A defective RNA satellite virus (viroid-like) requiring helper function of HBV for its expression and pathogenicity but not for its replication

b. Only one serotype recognized, eight genotypes

c. 35- to 37-nm spherical particle, enveloped by HBV lipoprotein coat (HBsAg)
image 19-nm corelike structure

d. Containing an antigenic nuclear phosphoprotein (HDV antigen)
image Binds RNA

image Exists in two isoforms: smaller 195 amino acid and larger 214 amino acid proteins

image Smaller HDV antigen transports RNA into the nucleus: essential for HDV replication

image Larger HDV antigen prenylated: inhibits HDV RNA replication and participates in HDV assembly

e. HDV RNA, 1.7 kb, single stranded, covalently closed, and circular

f. HDV antigenome, a genome complementary, circular RNA found in infected hepatocyte and, to a much lesser extent, in purified HDV particles

g. HDV RNA the smallest RNA genome among the animal viruses; HDV resembling plant satellite viruses

h. RNA genome can form an unbranched rodlike structure by folding on itself through intramolecular base pairing

i. Replication limited to hepatocytes

j. Primary chimpanzee, woodchuck, and human hepatocellular carcinoma cell lines transfected with HDV cDNA constructs expressing HDV RNA and HDV antigens

3. HCV
a. A glycoprotein enveloped, single-stranded RNA virus

b. 55- to 60-nm spherical particle; 33-nm nucleocapsid core

c. Classified among the Flaviviridae, in the hepacivirus genus

d. HCV genome comprises approximately 9.4 to 9.6 kb, encoding a large polyprotein of approximately 3000 amino acid residues
image One third of the polyprotein consisting of a series of structural proteins (an internal nucleocapsid or core [C] protein and two glycosylated envelope proteins, termed E1 and E2, present in the lipid-containing envelope of the virus)

image Envelope proteins possibly generating neutralizing antibodies

image A hypervariable region localized in E2

image Remaining two thirds of the polyprotein consisting of nonstructural proteins (termed NS2, NS3, NS4A, NS4B, NS5A, and NS5B) involved in HCV replication: a zinc-dependent metalloproteinase in NS2/3, a nucleotide triphosphatase/helicase in NS3, a chymotrypsin-like serine protease in NS3-4A, RNA-dependent RNA polymerase in NS5B, an interferon sensitivity region in NS5A, and an ion channel, P7

e. Only one HCV serotype identified; six major HCV genotypes with multiple subtypes; genotypes variably distributed throughout the world

f. Genotypes correlated with likelihood of response of chronic infection to antiviral therapy and duration of therapy


Epidemiology and Risk Factors



HAV



1. Incubation period: 15 to 50 days (average, 30 days)

2. Worldwide distribution; highly endemic in developing countries

3. HAV excreted in stools of infected persons for 1 to 2 weeks before and for at least 1 week after onset of illness

4. Viremia short-lived, usually no longer than 3 weeks; occasionally up to 90 days in protracted or relapsing infection

5. Prolonged fecal excretion (months) reported in infected neonates; frequency, level of virus in stool, and epidemiologic importance uncertain

6. Enteric (fecal–oral) transmission predominantly by person-to-person household spread; occasional outbreaks linked to common-source vehicles:
image Contaminated food, bivalve mollusks, water

7. Other risk factors including exposure:
image In day care centers for infants, diapered children

image In institutions for developmentally disadvantaged

image Through international travel to developing countries (most common risk factor in U.S.)

image Through oral–anal homosexual behavior or multiple sexual contacts

image Through shared equipment/drugs by injection drug users

8. No evidence for maternal–neonatal transmission

9. Prevalence correlated with sanitary standards and large household size

10. Transmission by blood transfusion or blood products: very rare

11. No risk factor identified in 30% to 40% of cases in the United States

11. Overall seroprevalence in the United States: less than 30% and declining rapidly with expanded vaccine use

12. Increased disease severity in individuals with preexisting liver disease or age 40 years or older


HEV



1. Incubation period: approximately 40 days (range, 15 to 65 days)

2. Widely distributed; epidemic and endemic forms but symptomatic infections rare in the United States; nonetheless, seroprevalence in U.S. population of approximately 21%

3. HEV RNA in serum and stool during acute phase

4. Most common form of sporadic hepatitis in young adults in the developing world

5. Largely water-borne outbreaks in Asia, Africa, and Central America

6. Intrafamilial, secondary cases uncommon

7. Maternal–neonatal transmission documented

8. In the United States, imported cases in returning travelers, in recent immigrants from endemic regions; sporadic, rare cases of transmission through undercooked pork products, liver or other organ meats, shellfish, or venison or by transfusion

9. Prolonged viremia or fecal shedding unusual; continued viral shedding possible in rare cases in organ transplant recipients in whom chronic hepatitis develops

10. Genotypes 1 and 2 isolated from sporadic human cases and water-borne outbreaks; genotypes 3 and 4 in swine and other animals and apparently transmitted zoonotically


HBV



1. Incubation period: 15 to 180 days (average, 60 to 90 days)

2. HBV viremia lasting for weeks to months after acute infection

3. 1% to 5% of adults, 90% of infected neonates, and 50% of infants developing chronic infection and persistent viremia

4. Persistent infection linked to chronic hepatitis, cirrhosis, hepatocellular carcinoma, and premature mortality

5. Persistent infection linked to acute necrotizing vasculitis, membranous glomerulonephritis

6. Worldwide distribution: HBV carrier prevalence less than 1% in the United States, 5% to 15% in Asia and sub-Saharan Africa; declining incidence in areas where vaccine use has expanded

7. HBV present in blood, semen, cervicovaginal secretions, saliva, and other body fluids

8. Risk of HBV infection highly correlated with HBV DNA level and presence of HBeAg

9. Increased disease severity in individuals with preexisting liver disease

10. Modes of transmission:
a. Blood-borne transmission
image Transfusion of blood/blood products

image Injecting drug users

image Hemodialysis recipients

image Health care and other workers exposed to blood

b. Sexual transmission: responsible for 50% of acute cases in the United States

c. Tissue penetrations (percutaneous) or permucosal transfer
image Needlestick accidents

image Reuse of contaminated medical equipment

image Shared razor blades

image Tattoos

image Acupuncture, body piercing

image Shared toothbrushes

d. Maternal–neonatal, maternal–infant transmission

e. No evidence for fecal–oral spread

f. No risk factor identified in 25% of cases


HDV



1. Incubation period: estimated to be 4 to 7 weeks

2. Endemic in Mediterranean basin, Balkan peninsula, Central Europe, parts of Africa, Middle East, and Amazon basin

3. Declining incidence with increasing use of HBV vaccine

4. HDV infection in 2% to 5% of patients with chronic hepatitis B in the United States

5. Viremia short-lived (acute infection) or prolonged (chronic infection)

6. HDV infections occurring solely in individuals at risk for HBV infection (coinfections or superinfections)

7. Modes of transmission
a. Blood-borne transmission
image Injection drug use the predominant mode of spread in the United States

image Recipients of high-risk blood products

b. Sexual transmission
image Homosexual or bisexual adolescents and men

image Sexual partners

c. Maternal–neonatal spread, but frequency uncertain


HCV



1. Incubation period: 15 to 160 days (major peak at approximately 50 days)

2. Prolonged viremia and persistent infection common (55% to 85%); wide geographic distribution

3. Persistent infection etiologically linked to chronic hepatitis, cirrhosis, hepatocellular carcinoma and premature death

4. Seroprevalence of past/present infection 1.3% in the United States, approaching 20% in some communities in Italy and Japan, and up to 40% in some villages in the Nile delta of Egypt

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Jun 4, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Acute viral hepatitis

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