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

Hepatitis Review

 

A

B

C

D

E

Source

stool

Blood/blood derived body fluids

Blood/blood derived body fluids

Blood/blood derived body fluids

stool

Route

Fecal-oral

Skin, mucous membranes

Skin, mucous membranes

Skin, mucous membranes

Fecal-oral

Chronicity

No

Yes

Yes

Yes

No

Prevention

Pre/post

Pre/post

Blood donor screen, risk behavior modification

Pre/post exposure immuniz., risk behavior modification

Safe potable

exposure

exposure

water

immuniz.

immuniz.

Hepatitis A in history

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

Electron microscopy of Hepatitis A virus. CDC.

Electron microscopy of Hepatitis A virus. CDC.

Hepatitis A: Pathophysiology

Hepatocellular injury pattern

Diffuse liver necrosis Prominent centrilobular damage Increased portal cellularity Regional lymph node enlargement, splenomegaly

Cholestasis: jaundice and hyperbilirubinemia Impaired hepatic synthetic function: decreased albumin, prolonged PT

Hepatits A: Pathophysiolgy

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

Hepatitis A Replication

Hepatitis A Replication

Hepatitis A: Frequency

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 Worldwide: nearly endemic (~100% past childhood)

Africa, Asia, and Central and South America with the Middle East having a particularly high prevalence of HAV infection

Hepatitis A: Morbidity/Mortality

Self-limited Lacks chronicity 0.4% case fatality rate (HAV associated fulminant hepatitis) HAV vertical transmission, blood transfusion transmission:

very rare HAV transmission from nonhuman primate to human has occured

Hepatitis A: Age Association

Children 5 to 14 yo form majority of cases

Typically not diagnosed: similar to acute gastroenteritis, anicteric

Hepatitis A: Clinical Presentation

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

Hepatitis A. Time course of infection.
Hepatitis A. Time course of infection.

Hepatitis A: Virology

Picornavirus (enterovirus) group

7.5-kb RNA icosahedral nonenveloped virus with a diameter of 27 nm. The virus has 1 serotype but multiple genotypes

Single-stranded, positive-sense, linear RNA virus Resistance to denaturation No antibody cross-reactivity has been identified with other viruses causing acute hepatitis

Hepatitis A: Diagnosis

Elevation of transaminases:

ALT, AST 4 to 100x ULN (may precede clinical presentation, peak within 3 to 10 days of onset of clinical illness) Bilirubin mildly elevated (less than 10 mg/dl, peak after 1 to 2 weeks of clinical illness)

Anti-HAV ab tests:

Anti-HAV IgM: acute, elevated up to 8 weeks, disappear by 6 months usually Anti-HAV IgG: levels increase inversely to anti-HAV IgM, persists lifelong, confers immunity

Imaging: not required, RUQ U/S for suspicion of cholelithiasis 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

Supportive only Contact isolation (fecal shedding) for one week post onset of illness Follow up LFT’s at monthly intervals to resolution

Hepatitis A: Treatment

Immunization: HAV immune globulin (IG), HAV vaccine

IG: IM, up to 90% effective by passive immunity HAV vaccine: at 1 mo, 6 mo (respectively, 99% and 100% seroconversion) Pre-exposure prophylaxis: travel to endemic areas, <2wk trip, <2 yo, then IG; >3mo trip (and can’t receive vaccine), then larger dose of IG; otherwise, HAV vaccination Post-exposure prophylaxis: IG administration up to 2 weeks post exposure: household, sexual liasons, daycare, food handlers, etc.

Hepatitis A: Complications

Relapsing hepatitis A virus infection

3-20% of patients , multiple relapses Remission phase occurs, with partial or complete resolution of clinical and biochemical manifestations. 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 Greater cholestasis as well as vasculitic skin rashes and nephritis

Hepatitis A: Complications

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

Corticosteroids may predispose patients to developing relapsing hepatitis A?

Liver transplantation: significant decompensation

Recurrent disease does not occur following liver transplantation despite immunosuppression

Hepatitis A: Complications

Acute renal failure Interstitial nephritis Pancreatitis Red blood cell aplasia, agranulocytosis, bone marrow aplasia Transient heart block Guillain-Barré syndrome, acute arthritis, Still disease, lupuslike syndrome, and Sjögren syndrome Autoimmune hepatitis following hepatitis A virus infection? Case reports only.

These complications are all rare

Hepatitis D

1977: Mario Rizzetto and colleagues discovered HDV, also known as the delta virus Single-stranded, 1.7-kb RNA virus Co-infection with Hepatitis B required for packaging and release of HDV virions from infected hepatocytes 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

Turin, Italy – Hepatitis D Site of discovery 1977 Geosystems Global Corporation

Hepatitis D

Three known genotypes are described

Genotype I has a worldwide distribution Genotype 2 has been discovered in Taiwan, Japan, and northern Asia Genotype 3 is found in South America

Hepatitis D: Prevalence, Transmission

HDV infects 5% of the world's 300 million HBsAg carriers Prevalence of HDV infection in South America and Africa is high with Italy and Greece being areas of intermediate endemicity HDV in prostitutes in Greece and Taiwan is high IVDA most common mode of transmission: 17% to 90% co- infected

Source: Perrotta, Anne T.; Been, Michael D. "A pseudoknot-like structure required for efficient self-cleavage of

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

Mirrors acute Hepatitis B alone: mild to severe Risk of developing chronic HBV and HDV infection after acute exposure to both viruses is the same (~5%) Chronic HBV and HDV disease tends to progress more rapidly to cirrhosis than chronic HBV infection alone HDV superinfection may result in fulminant hepatic failure Greater than 60% can become cirrhotic

HBV-HDV coinfection

1 ACUTE HEPATITIS

Symptoms:

Preicteric phase: fatigue, lethargy, anorexia, nausea, headache for 3-7 days Icteric phase: jaundice, fatigue and nausea - clay- colored stools and dark urine. often asymptomatic Incubation period of 3 to 7 weeks manifested in single episode (simultaneous HBV/HDV replication) or in two episodes (sequential HBV/HDV replication) Disease is over in 6 months HBV-HDV coinfection could lead to more severe cases than HBV-only infection Higher incidence of fulminant hepatitis Low incidence of chronic hepatitis (1-3%)

Superinfection More Common / More Serious

2 FULMINANT HEPATITIS Symptoms jaundice, coagulopathy hepatic encephalopathy -changes in personality, disturbances in sleep, confusion, difficulty concentrating, occasionally abnormal behavior severe, rare form of viral hepatitis results in acute, massive destruction of large portions of the liver Mortality: 80% indication for orthotopic liver transplantation ten times more likely than HBV-only cases

of the liver Mortality: 80% indication for orthotopic liver transplantation ten times more likely than HBV-only
of the liver Mortality: 80% indication for orthotopic liver transplantation ten times more likely than HBV-only

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

leads to liver failure and portal hypertension Death results from bleeding, hepatic coma, infection, or kidney
FIGURE from Fields Virology, 5th ed, 3039. Acute hepatiti s D progressing to chronic he

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

Hepatitis D: Histopathology

Same as chronic HBV:

classic histologic abnormalities:

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) 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 Ground-glass cells: the granular homogeneous eosinophilic staining of cytoplasm caused by the presence of HBsAg Sanded nuclei reflect the presence of an overload of HBcAg

Hepatitis D: Diagnosis

Serologic diagnosis of HDV infection:

 

Results are positive for HDV antigen in 20%

Results are positive for HDV RNA in 90% with the reverse transcriptase polymerase chain reaction

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 anti-

HDV 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

In summary:

HBcAb IgM distinguishes between coinfection (HBcAb IgM–positive) and superinfection (HBcAb IgM–negative)

HDV Treatment Options

HBV & HDV coinfection:

Less responsive to interferon therapy than patients infected with HBV alone Lamivudine appears to be ineffective against HBV/HDV coinfection

Hepatitis E

1983: HEV particles were first recovered from the stool of patients in Tashkent, Uzbekistan Retrospectively discovered to be cause of prior waterborne enterically transmitted epidemics of NANB hepatitis

South, Southeast, and Central Asia Africa and Mexico

Hepatitis E

HEV is a calicivirus A 7.5-kb single-stranded 32-34 nm RNA virus Incubation period of 2-9 weeks 1990: cloning of the HEV Lesser-developed countries Anti-HEV antibodies: up to 60% of Indian children younger than 5 years Sporadic infections among Westerners traveling in endemic areas

Electron microscopy of Hepatitis E virus. Obtained from the CDC Public Health Image Library .

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

Hepatitis E

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

HEV does not appear to cause chronic liver disease

Pregnant women at risk

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

Hepatitis E: Histopathology

Infiltration of portal tracts by lymphocytes and polymorphonuclear leukocytes Ballooned hepatocytes, acidophilic body formation, and the intralobular necrosis of hepatocytes Submassive and massive hepatic necrosis in severe cases

Hepatitis E: Diagnosis, Treatment

Serologic diagnosis:

IgM anti-HEV and IgG anti-HEV HEV RNA can be detected in the serum and stool of infected patients

Supportive Treatment

That’s all, Folks…
That’s all, Folks…

References

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.