Hepatitis A, D, E

An Overview
Core Curriculum Lecture
10 November 2009
Typhanie Kinder
Attending: Alexander Kuo, M.D.

Hepatitis Review
A

Source

stool

Blood/blood Blood/blood Blood/blood stool

derived body derived body derived body
fluids
fluids
fluids

Route

Fecal-oral

Skin, mucous Skin, mucous Skin, mucous Fecal-oral

membranes membranes membranes

Chronicity

No

Yes

Yes

Yes

No

Prevention

Pre/post
exposure
immuniz.

Pre/post
exposure
immuniz.

Blood donor
screen, risk
behavior
modification

Pre/post
exposure
immuniz.,
risk behavior
modification

Safe potable
water

Hepatitis A in history
Military scourge from the 2nd century: jaundice outbreaks
y 1st modern description: WWII, labeled as infectious hepatitis
and observations insinuated a fecal-oral route of transmission
y 1950s: Hepatitis A and B mode of transmission confirmed at the
Willowbrook State School in Staten Island, NY
y 1973: Hepatitis A virions first identified in the stool of patients by
electron microscopy allowing future serologic testing discovery
y

Electron microscopy of Hepatitis A virus. CDC.

Hepatitis A: Pathophysiology
y Hepatocellular injury pattern

Diffuse liver necrosis

y Prominent centrilobular damage
y Increased portal cellularity
y Regional lymph node enlargement, splenomegaly
y

y Cholestasis: jaundice and hyperbilirubinemia

y Impaired hepatic synthetic function: decreased albumin,

prolonged PT

Hepatits A: Pathophysiolgy
y Transmission: fecal-oral with hepatic viral replication, then

HAV bile excretion with highest infectivity correlating with

highest stool concentration 2 weeks before jaundice noted

Hepatocyte uptake involves a receptor on the plasma

membrane of the cell
y Viral replication is believed to occur exclusively in hepatocytes
y After entry into the cell, viral RNA is uncoated, and host
ribosomes bind to form polysomes
y Viral proteins are synthesized
y The viral genome is copied by a viral RNA polymerase
y Assembled virus particles are shed into the biliary tree and
excreted in the feces
y

Hepatitis A Replication

Hepatitis A: Frequency
y Endemic in U.S. population subsets: prisons, institutions,

daycares, certain ethnic and lower socio-economic groups

(American Indians, Alaskan natives)
U.S. prevalence: 1/3 of adults have serologic evidence of pior
infection
y Worldwide: nearly endemic (~100% past childhood)
y

y Africa, Asia, and Central and South America with the Middle East having

a particularly high prevalence of HAV infection

Hepatitis A: Morbidity/Mortality
y Self-limited
y Lacks chronicity
y 0.4% case fatality rate (HAV associated fulminant hepatitis)
y HAV vertical transmission, blood transfusion transmission:

very rare
y HAV transmission from nonhuman primate to human has
occured

Hepatitis A: Age Association

y Children 5 to 14 yo form majority of cases
y

Typically not diagnosed: similar to acute gastroenteritis,

anicteric

Hepatitis A: Clinical Presentation

y Incubation period of HAV is 15-45 days (average, 4 wk)
y Rarely severe
y Malaise, anorexia, nausea, vomiting
y RUQ tenderness
y Jaundice: 2/3
y Splenomegaly: up to 20%

Hepatitis A. Time course of infection.

Hepatitis A: Virology
y Picornavirus (enterovirus) group
y

7.5-kb RNA icosahedral nonenveloped virus with a diameter of

27 nm. The virus has 1 serotype but multiple genotypes

y Single-stranded, positive-sense, linear RNA virus

y Resistance to denaturation
y No antibody cross-reactivity has been identified with other

viruses causing acute hepatitis

Hepatitis A: Diagnosis
y Elevation of transaminases:
y ALT, AST 4 to 100x ULN (may precede clinical presentation, peak within 3

to 10 days of onset of clinical illness)

y Bilirubin mildly elevated (less than 10 mg/dl, peak after 1 to 2 weeks of
clinical illness)
y Anti-HAV ab tests:
y Anti-HAV IgM: acute, elevated up to 8 weeks, disappear by 6 months

usually
y Anti-HAV IgG: levels increase inversely to anti-HAV IgM, persists lifelong,
confers immunity
y Imaging: not required, RUQ U/S for suspicion of cholelithiasis
y Histology: liver biopsy not required (inflammatory cell infiltration--

mononuclear cell infiltrate, interface hepatitis, focal hepatocyte

dropout, ballooning degeneration, and acidophilic (Councilman-like)
bodies, hepatocellular necrosis, liver cell regeneration)

Hepatitis A: Treatment
y Supportive only
y Contact isolation (fecal shedding) for one week post onset of

illness
y Follow up LFTs at monthly intervals to resolution

Hepatitis A: Treatment
y Immunization: HAV immune globulin (IG), HAV vaccine

IG: IM, up to 90% effective by passive immunity

y HAV vaccine: at 1 mo, 6 mo (respectively, 99% and 100%
seroconversion)
y Pre-exposure prophylaxis: travel to endemic areas, <2wk trip,
<2 yo, then IG; >3mo trip (and cant receive vaccine), then
larger dose of IG; otherwise, HAV vaccination
y Post-exposure prophylaxis: IG administration up to 2 weeks
post exposure: household, sexual liasons, daycare, food
handlers, etc.
y

Hepatitis A: Complications
y Relapsing hepatitis A virus infection

3-20% of patients , multiple relapses

y Remission phase occurs, with partial or complete resolution of
clinical and biochemical manifestations.
y The initial flare usually lasts 3-6 weeks; relapse occurs after a
short period (usually <3 wk) and mimics the initial
presentation, although it usually is clinically milder
y Greater cholestasis as well as vasculitic skin rashes and nephritis
y

Hepatitis A: Complications
During relapses, shedding of virus can be detected and IgM
antibody test findings are positive
y The clinical course is toward resolution, with lengthening
periods between flares and a total duration of 3-9 months
y Corticosteroid treatment has been shown to improve the
clinical course, although generally benign without treatment
y

y Corticosteroids may predispose patients to developing relapsing hepatitis

A?
y

Liver transplantation: significant decompensation

y Recurrent disease does not occur following liver transplantation despite

immunosuppression

Hepatitis A: Complications
y Acute renal failure
y Interstitial nephritis
y Pancreatitis
y Red blood cell aplasia, agranulocytosis, bone marrow aplasia
y Transient heart block
y Guillain-Barr syndrome, acute arthritis, Still disease,

lupuslike syndrome, and Sjgren syndrome

y Autoimmune hepatitis following hepatitis A virus infection?
Case reports only.
y

These complications are all rare

Hepatitis D
y 1977: Mario Rizzetto and colleagues discovered HDV, also

known as the delta virus

y Single-stranded, 1.7-kb RNA virus
y Co-infection with Hepatitis B required for packaging and
release of HDV virions from infected hepatocytes
y Viral particle is 36 nm in diameter and contains HDAg and
the RNA strand, using HBsAg as its envelope protein

Turin, Italy Hepatitis D Site of

discovery 1977
Geosystems Global Corporation

Hepatitis D
y Three known genotypes are described

Genotype I has a worldwide distribution

y Genotype 2 has been discovered in Taiwan, Japan, and northern
Asia
y Genotype 3 is found in South America
y

Hepatitis D: Prevalence, Transmission

y HDV infects 5% of the world's 300 million HBsAg carriers
y Prevalence of HDV infection in South America and Africa is

high with Italy and Greece being areas of intermediate

endemicity
y HDV in prostitutes in Greece and Taiwan is high
y IVDA most common mode of transmission: 17% to 90% coinfected

Source: Perrotta, Anne T.; Been, Michael D. "A pseudoknot-like structure required for
efficient self-cleavage of hepatitis delta virus RNA." Nature v350, n6317 (April 4, 1991):434.

Hepatitis D: Clinical Presentation

y Mirrors acute Hepatitis B alone: mild to severe
y Risk of developing chronic HBV and HDV infection after

acute exposure to both viruses is the same (~5%)

y Chronic HBV and HDV disease tends to progress more
rapidly to cirrhosis than chronic HBV infection alone
y HDV superinfection may result in fulminant hepatic failure
y Greater than 60% can become cirrhotic

HBV-HDV coinfection

Superinfection
More Common / More
Serious

2 FULMINANT
HEPATITIS
Symptoms:
Symptoms
Preicteric phase: fatigue,
jaundice, coagulopathy
lethargy, anorexia, nausea, hepatic encephalopathy
headache for 3-7 days
-changes in personality,
Icteric phase: jaundice,
disturbances in sleep,
fatigue and nausea - clayconfusion, difficulty
colored stools and dark
concentrating, occasionally
urine.
abnormal behavior
often asymptomatic
severe, rare form of viral
Incubation period of 3 to 7 hepatitis
weeks
results in acute, massive
manifested in single episode destruction of large portions
(simultaneous HBV/HDV of the liver
replication) or in two
Mortality: 80%
episodes (sequential
indication for orthotopic
HBV/HDV replication)
liver transplantation
Disease is over in 6 months
ten times more likely than
HBV-HDV coinfection could
HBV-only cases
lead to more severe cases
than HBV-only infection
Higher incidence of
fulminant hepatitis
Low incidence of chronic
hepatitis (1-3%)
1 ACUTE HEPATITIS

Large numbers of hepatocytes are already producing

HBsAg
HDV replicates faster (incubation 3 weeks)
Fatality rates from fulminant hepatitis up to 20%
3 CHRONIC TYPE D HEPATITIS
Almost all superinfection cases proceed to chronic
hepatitis
Symptoms
similar to acute hepatitis but less severe
ongoing liver inflammation
70-80% develop cirrhosis compared to 15-30% with only
chronic HBV infection
Cirrhosis leads to liver failure and portal hypertension
Death results from bleeding, hepatic coma, infection, or
kidney failure

FIGURE from Fields Virology, 5th ed, 3039. Acute hepatitis D progressing to chronic hepatitis B virus infection.

Hepatitis D: Histopathology
y Same as chronic HBV:
y

classic histologic abnormalities:

y Inflammatory infiltrates: mononuclear cells may either remain contained

within the portal areas or disrupt the limiting plates of portal tracts,
expanding into the liver lobule (interface hepatitis)
y Periportal fibrosis or bridging necrosis (between portal tracts) may be
present with the presence of bridging necrosis places the patient at
increased risk for progression to cirrhosis
y Ground-glass cells: the granular homogeneous eosinophilic staining of
cytoplasm caused by the presence of HBsAg
y Sanded nuclei reflect the presence of an overload of HBcAg

Hepatitis D: Diagnosis
y Serologic diagnosis of HDV infection:
y Results are positive for HDV antigen in 20%
y Results are positive for HDV RNA in 90% with the reverse transcriptase polymerase chain reaction
y
y
y
y
y
y

being the most sensitive assay for the detection of HDV viremia
Results for anti-HDV immunoglobulin M (IgM) are positive initially and then are positive for antiHDV immunoglobulin G
The finding of antigen A antibody to HDV is almost exclusively associated with chronic HDV
infections
Results for anti-HB core IgM are positive, except with superinfection, in which anti-HB core IgM is
absent
ALT, AST levels greater than 500 IU/L
INR greater than 1.5 or a PT greater than 17 seconds may be the first evidence of fulminant liver
failure
HBsAg is required for HDV replication but may be suppressed to undetectable levels with active HDV
replication

y In summary:
y HBcAb IgM distinguishes between coinfection (HBcAb IgMpositive) and superinfection (HBcAb

IgMnegative)

HDV Treatment Options

y HBV & HDV coinfection:

Less responsive to interferon therapy than patients infected

with HBV alone
y Lamivudine appears to be ineffective against HBV/HDV
coinfection
y

Hepatitis E
y 1983: HEV particles were first recovered from the stool of

patients in Tashkent, Uzbekistan

y Retrospectively discovered to be cause of prior waterborne
enterically transmitted epidemics of NANB hepatitis
South, Southeast, and Central Asia
y Africa and Mexico
y

Hepatitis E
y HEV is a calicivirus
y A 7.5-kb single-stranded 32-34 nm RNA virus
y Incubation period of 2-9 weeks
y 1990: cloning of the HEV
y Lesser-developed countries
y Anti-HEV antibodies: up to 60% of Indian children younger

than 5 years
y Sporadic infections among Westerners traveling in endemic
areas

Electron microscopy of Hepatitis E virus. Obtained from the CDC Public Health Image Library.
Image credit: CDC/ (PHIL #5605)

Hepatitis E
y Adults and young adults
y Acute infection less severe than acute HBV infection
y Fluctuating aminotransferase levels

HEV does not appear to cause chronic liver disease

Pregnant women at risk
y in third trimester, up to a 25% risk of mortality associated with
acute HEV infection

Hepatitis E: Histopathology
y Infiltration of portal tracts by lymphocytes and

polymorphonuclear leukocytes
y Ballooned hepatocytes, acidophilic body formation, and the
intralobular necrosis of hepatocytes
y Submassive and massive hepatic necrosis in severe cases

Hepatitis E: Diagnosis, Treatment

y Serologic diagnosis:

IgM anti-HEV and IgG anti-HEV

y HEV RNA can be detected in the serum and stool of infected
patients
y

y Supportive Treatment

Thats all, Folks

References
y

Aggarwal R, Shahi H, Naik S, Yachha SK, Naik SR. Evidence in favor of high infection rate with hepatitis E virus among young
children in India. J Hepatol. Jun 1997;26(6):1425-6.

Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: Recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. Oct 1 1999;48:1-37.

Farci P. Delta hepatitis: an update. J Hepatol. 2003;39 Suppl 1:S212-9.

Gordon SC, Reddy KR, Schiff L, et al. Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann Intern
Med. Nov 1984;101(5):635-7.

Lau DT, Doo E, Park Y, et al. Lamivudine for chronic delta hepatitis. Hepatology. Aug 1999;30(2):546-9

Keeffe EB. Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases?. Am J
Gastroenterol. Feb 1995;90(2):201-5.

Kemmer NM, Miskovsky EP. Hepatitis A. Infect Dis Clin North Am. Sep 2000;14(3):605-15.

Tadataka Y. Textbook of Gastroenterology. Vol 1. Lippincott Williams & Wilkins; 1999.

Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic
hepatitis C. N Engl J Med. Jan 29 1998;338(5):286-90.