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with intramuscular serum immune Clinical Manifestations Elevated LFTs are an indication of
globulingiven within two weeks of The clinical manifestations encom- necroinflammation and represent the
exposurewill also provide protection pass a wide spectrum in the acute as well biochemical markers. An elevated PT,
against this virus. as the chronic state. The virus has an in conjunction with a low albumin,
incubation period of two to six weeks. usually indicates a poor prognosis or
Up to 70% of the acute cases present as chronicity.
Vaccinations
a subclinical anicteric state, and the Histologic examination by liver bi-
The current epidemic of hepatitis A
remainder present with jaundice, nausea opsy is the most specific and accurate
could be avoided though a worldwide
and vomiting, fevers, right upper quad- indicator of liver disease. Most individ-
viral campaign. The vaccines are safe,
rant pain, and hepatomegaly or fulmi- uals do not need a biopsy for diagnosis
efficacious, and relatively inexpensive.
nant hepatic failure. Some of these can or prognosis. However, some individual
The live, attenuated vaccine is no longer
also present with extra hepatic manifes- with normal LFTs, and elevated HBV
in use because of the superiority of the
tations. DNA levels have substantial fibrosis on
inactivated vaccines. Therefore, the in-
If the LFTs are still elevated after six biopsy.7
activated vaccines are the only Food and
Drug Administration (FDA)-approved months, then the individual is consid-
vaccines that are used in the United ered to have a chronic HBV infection, Treatment of HBV
States. The inactivated vaccine provides but most patients with chronic hepatitis The goals of HBV treatment are to
almost a 100% seroconversion rate and B are asymptomatic. 1) prevent cirrhosis and its complica-
a higher antibody response than even tions; 2) prevent hepatocellular carcino-
serum immune globulin. ma; 3) obtain undetectable HBV DNA
Diagnostic Markers levels; 4) normalize LFTs; 5) eradicate
The diagnosis of HBV is based on
HBeAg; and 6) improve histology. The
the clinical presentation (complete his- dilemma is that the above aims are
HEPATITIS B tory and physical); serologic, virologic, difficult to achieve because no standard
and biochemical markers; and occasion- treatment algorithms, guidelines, or
Epidemiology ally histologic markers. Hepatitis B treatment endpoints exist and because,
Hepatitis B virus (HBV) is a global surface antigen (HBsAg) is the first patients usually present with conflicting
problem, with .350 million carriers serologic marker to appear after in- data. Treatment should be considered
worldwide and 1.25 million in the fection. Hepatitis B e antigen for individuals who are HBsAg-positive
United States. An estimated 100,000 (HBeAg) indicates active viral replica- or DNA-positive by PCR.8 The care of
acute infections occur every year in the tion, which makes a patient highly the patient with normal ALT adds
United States. The mortality is sub- contagious. Hepatitis B core antibody a further dilemma to the treatment
stantial; each year 5000 patients in the (HBcAb) appears next and implies an options. With or without treatment,
United States and .1 million world- acute or chronic state or early recovery circulating HBsAg can disappear but
wide die. In high-prevalence areas, the period. Hepatitis B surface antibody HBV DNA can be found by PCR in the
predominant mode of transmission is (HBsAb) is the last to appear and liver of many individuals.9,10 Regardless
perinatal, while in low-prevalence areas implies recovery, immunity, or the of the treatment, many experts believe
it is by sexual transmission and in- post-vaccine state. that chronic HBV infection can be
travenous drug use.5 Blood transfusions Hepatitis B virus (HBV) DNA is controlled but not cured.
are another source of spread of HBV, a virologic marker that measures the Agents used to treat HBV include
which remains the number one trans- level of viral replication. In the past, this interferon, lamivudine, adefovir, ente-
mitted blood-borne virus in the health- was measured by nonamplified hybrid- cavir, and telbivudine.11 Tenofovir is
care environment.6 ization assays, which have been replaced approved to treat HIV and HBV co-
Individuals with HBV are at risk of by the current target amplification infection only. The Asian-Pacific guide-
developing chronic infection, cirrhosis, assays, such as polymerase chain re- lines also include thymosin alpha, which
hepatic decompensation, and hepatocel- action (PCR). Hepatitis B virus (HBV) is not an FDA-approved drug.
lular carcinoma. After the acute in- has eight genotypes (AH) based on Interferon was the first drug used to
fection, 3%5% of adults and up to DNA sequencing and geographic distri- treat HBV in most countries and has
95% of children fail to produce a suffi- bution. However, genotype testing is antiviral, antiproliferative, and immu-
cient immune response to clear the not used in clinical practice because its nomodulatory effects; in addition, it can
infection,5 thus going on to chronic relevance remains uncertain and con- achieve a durable response after a finite
hepatitis B. troversial. course of treatment (2452 weeks). In
general, elevated LFTs and low HBV extent than lamivudine and adefovir. It transmissions are tattoos, body piercing,
DNA are the best predictors of treat- is associated with a low rate of drug and intranasal cocaine use.
ment response.12 Interferon therapy, resistance, and the duration of therapy is HCV is a small RNA virus with six
however, is costly, must be given by greater than one year. Entecavir has few genotypes and was first identified in
injection, and has many side effects. side effects, but like lamivudine, it has 1989. Genotype 1 accounts for 70%
The nucleoside/nucleotide analogues are a black box warning as a potential cause 75% of all HCV infections in the
more potent than interferon in suppres- of lactic acidosis, hepatomegaly, and United States. It is the most common
sing the HBV DNA levels and can lead steatosis. blood-borne infection in the United
to undetectable levels by PCR; however, Tenofovir is a nucleotide analog States, and the highest prevalence is in
interferon has immunmoduatory effects similar to adefovir, but it is more persons aged 3049 years old. In this
and is the only drug associated with potent. It is effective against HIV and age group, the highest prevalence occurs
HBVsAg conversion.13,14 HBV and should only be used in co- in African Americans.17
Interferon usually causes a flare in infection with both diseases. Most acutely infected patients are
the ALT level because of immune- Telbivudine is a nucleoside analogue asymptomatic or have a subclinical in-
mediated lyses of the hepatocytes. This that was recently approved by the FDA. fection without jaundice. Chronic HCV
response, coupled with a later normal- It is administered orally (600 mg/day) infection develops in 60%80% of
ization of LFTs and a decrease in and might suppress HBV DNA levels infected persons, probably secondary
inflammation, heralds a good prognosis. to a greater extent than the previous to rapid mutations that cause a failure
Polyethylene glycol (PEG) is at- medications. in T-cell immune recognition. Hepatitis
tached to the interferon molecule to C virus (HCV) is the number one cause
decrease its rate of absorption and renal HBV Prevention of chronic liver disease, cirrhosis, and
and cellular clearance, which increases There are more than 350 million liver transplantation in the United
its half-life. This characteristic has pro- carriers worldwide with HBV and States.
pelled PEG-interferon as the drug of almost one million deaths per year.
choice over standard interferon.14 PEG- The greatest hope to prevent this disease
interferon is safe in compensated but is through primary prevention: safe Diagnostic Tests
not decompensated cirrhosis. sexual practices, intravenous drug avoid- Hepatitis C virus (HCV) DNA in
Lamivudine, a nucleoside analog, ance, and vaccination to increase herd the serum or liver is the first sign of
was originally used to treat HIV disease. immunity. The HBV vaccine is safe, is infection. The virus becomes positive in
For HBV, it is well tolerated, is given relatively inexpensive, has a high sero- tests days to weeks after exposure. This
orally (100 mg/day), is relatively in- conversion rate, and is given in three test detects, quantifies, and characterizes
expensive ($7/day), has minimal side doses intramuscularly. the viral particle components. This test
effects, and can be used in decompen- is further broken down into a qualitative
sated cirrhosis; however, it is associated and a quantitative test. The qualitative
with a high rate of drug resistance. HEPATITIS C test is more sensitive, 98%99% specif-
Adefovir, a nucleotide analog of ic, and is done by either PCR or by
adenosine, can be used in HBeAg- Epidemiology transcription-mediated amplification
positive or HBeAg-negative patients Hepatitis C infection affects .170 (TMA). The quantitative test can detect
and with compensated or decompen- million people worldwide and .4 ,50 copies of the virus and is done by
sated cirrhosis. Its route of administra- million Americans, but most are asymp- either PCR, TMA, or branched chain
tion is oral (10 mg/day) at a cost of tomatic and unaware of their disease.16 DNA (bDNA).
$15$20/day. It has a low rate of drug Most patients acquired HCV by in- The indirect tests (HCV and geno-
resistance, but its duration of therapy is jection drug use or through pre-1990 typing) detect antibodies. The third-
greater than one year, and the dose blood transfusions. In the 1980s, generation enzyme assay detects HCV
needs to be adjusted in renal insuf- 230,000 new cases were diagnosed each proteins. It becomes positive eight
fiency. Adefovir can be added to year in the United States, but now only weeks after exposure and detects 99%
lamivudine in case of lamivudine re- 36,000 cases are diagnosed year because of immunocompetent individuals. The
sistance; therefore, most physicians pre- of decreased injection drug use and recombinant immunoblot assay now has
fer adefovir.15 increased awareness. The risk of trans- limited utility thanks to this third
Entecavir is a nucleoside analog that mission between monogamous partners generation test. HCV genotyping de-
is given orally at 0.51 mg/day that is low but rises with multiple sexual tects type-specific antibodies and pre-
suppresses HBV DNA levels to a greater partners. Rare forms of percutaneous dicts treatment response.
contaminated blood and blood prod- 3. Feinstone SM, Kapikian AZ, Purceli RH. United States, 1999 through 2002. Ann Intern
Hepatitis A: detection by immune electron Med. 2006;144(10):705714.
ucts. It has a worldwide distribution and
microscopy of a virus like antigen associated 17. Alter MJ, Kruszon-Moran D, Nainan OV, et
is especially common in blood donors in al. The prevalence of hepatitis C virus infection
with acute illness. Science. 1973;182:1026.
the United States. Because this virus 4. Wheeler C, Vogt TM, Armstrong GL, et al. in the United States, 1988 through 1994.
may not produce disease in humans, An outbreak of hepatitis A associated with N Engl J Med. 1999;341:556562.
blood is not routinely screened for green onions. N Engl J Med. 2005;353: 18. NIH Consensus Development Conference
HGV. 890897. Panel Statement: management of hepatitis C.
5. Lee W. Hepatitis B virus infection. Hepatology. 1997;26:2S10S.
Studies have found that in the 19. Seef LB, Hoofnagle JH. NIH Consensus
N Engl J Med. 1997;337:17331745.
United States, 10%20% of HGV Development Conference: management of
6. Gerberding JL. The infected health care
patients are also co-infected with provider. N Engl J Med. 1996;334:594. hepatitis C. Hepatology, 2002;(Suppl 1):S1.
HCV. Mounting evidence has also 7. Lai CL, Chien RN, Leung NW, et al. A one 20. Manns MP, McHutchison JG, Gordon SC, et
shown a protective role of HGV in year trial of lamivudine for chronic hepatitis B. al. Peginterferon alfa-2b plus ribavirin com-
pared with interferon alfa-2b plus ribavirin for
HIV patients.24,25 N Engl J Med. 1998;339:6168.
8. Yim HJ, Lok A. Natural history of chronic initial treatment of chronic hepatitis C:
hepatitis B virus infection: what we knew in a randomized trial. Lancet. 2001;358:
1981 and what we know in 2005. Hepatology. 958965.
CONCLUSION 2006;43(2 Suppl 1):S173S181. 21. Fried MW, Schiffman ML, Reddy K, et al.
Pegylated (40 kDa) interferon alfa-2a (PE-
9. Fong TL, DiBisceglie AM, Gerber MA, et al.
GASYS) in combination with ribavirin: effica-
The viral hepatic disorders are di- Persistence of hepatitis B virus DNA in the
cy and safety results from a phase II,
vided into the acute disorders (hepatitis liver after loss of HbsAg in chronic hepatitis B.
randomized, activity-controlled, multicenter
A, E, G) and those with acute and Hepatology. 1993;18:13131318.
study. Gastroenterology. 2001;120:A55 (ab-
10. Komori M, Yuki N, Nagaoka T, et al. Long-
chronic states (hepatitis B, C, D). They stract).
term clinical impact of occult hepatitis B virus
are spread by the fecal-oral route, 22. Davis GL, Wong JB, McHutchinson JG,
infection in chronic hepatitis B patients.
perinatally, percutaneously, through Manns MP. Early virologic response to
J Hepatology. 2001;35:798804.
treatment with peginterferon alfa-2b plus
blood or blood products, or by un- 11. Perrillo R, Gish R, Peters M, et al. Chronic
ribavirin in patients with chronic hepatitis C.
protected intercourse. Treatment is hepatitis B: a critical appraisal of current
Hepatology. 2003;38:645.
mostly supportive, although several approaches to therapy. Clin Gastroenterol
23. Bonino F, Heermann KH, Rizzetto M, et al.
Hepatol. 2006;4:233248.
medications are available, depending Hepatitis delta virus: protein composition of
12. Schiff ER. Treatment algorithm for hepatitis B delta antigen and its hepatitis B virus-derived
on the individual disorder. Prevention and C. Gut. 1993;34(Suppl 2):S148S149. envelope. J Virol. 1986;58:945.
is through proper sanitary conditions, 13. Wong DKH, Cheung AM, ORourke K, et al. 24. Xiang J, Wunschmann S, Diekema DJ, et al.
vaccination, and education on risk Effect of alpha-interferon treatment in patients Effect of coinfection with GB virus C on
factors. with hepatitis B antigen-positive chronic survival among patients with HIV infection.
hepatitis B: a meta-analysis. Ann Intern Med. N Engl J Med. 2001;345(10):707714.
1993;119:312323. 25. Tillmann HL, Heiken H, Knapik-Botai A, et
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ACKNOWLEDGMENTS Peginterferon alfa-2a alone, lamivudine alone, mortality among HIV-infected patients.
I thank Mrs. Westina Fernandes for her and the 2 in combination in patients with HBe N Engl J Med. 2001;345(10):715724.
administrative support and critical revision antigen-negative chronic hepatitis B. N Engl J
of this manuscript. Med. 2004;351:12061217.
15. Keeffe E, Dieterich D, Han S, et al. A
REFERENCES treatment algorithm for the management of AUTHOR CONTRIBUTIONS
1. AGA guidelines: evaluation of LFTs. Gastro- chronic hepatitis B virus infection in the Design concept of study: Hall
enterology. 2002;123:1364. United States. Clin Gastroenterol Hepatol. Manuscript draft: Hall
2. Pratt DS, Kaplan MM. Evaluation of abnor- 2004;2:87106. Administrative, technical, or material assis-
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