((Viral Hepatitis))
Definition
Viral hepatitis refers to the clinically important hepatotrophic viruses responsible for hepatitis A (HAV), hepatitis B (HBV), delta hepatitis (HDV), hepatitis C (HCV), and hepatitis E (HEV). Viral hepatitis has acute, fulminant, and chronic clinical forms defined by duration or severity of infection. Acute viral hepatitis is a systemic viral infection of up to but not exceeding 6 months in duration that produces inflammatory necrosis of the liver. Chronic viral hepatitis describes prolongation or continuation of the hepatic necroinflammatory process 6 months or more beyond the onset of the acute illness (1).

Hepatitis A
Mode of Transmission :
A- HAV infection is usually transmitted via the fecal-oral route (2).
B-Large-scale outbreaks due to contamination of food and drinking water can occur (2).
C-The period of greatest infectivity is 2 weeks before the onset of clinical illness; fecal shedding continues for 2-3 weeks after the onset of symptoms (2).
Clinical Course
A- HAV infection usually produces a self-limited disease with a low case-fatality rate. The disease takes three phases: incubation, acute hepatitis, and convalescence (1). Almost all cases of acute HAV hepatitis will resolve in 4-6 weeks (2).
B-Acute liver failure is relatively rare, but risk increases with age : 0.1% in patients younger than 15 years old to >1% in patients older than 40 years old (2).
C-HAV does not induce chronic hepatitis , chronic carriers or cirrhosis (2).
D--The clinical presentation of HAV infection is given in Table -1. The average incubation period is 28 days, with a range of 15 to 50 days (1).
TABLE 1. Clinical Presentation of Acute Hepatitis A (1).
Signs and symptoms
1-The preicteric phase brings nonspecific influenza-like symptoms consisting of anorexia, nausea, fatigue, and malaise 2-Abrupt onset of anorexia, nausea, vomiting, malaise, fever, headache, and right upper quadrant abdominal pain with acute illness
3- Icteric hepatitis is generally accompanied by dark urine, acholic (light-colored) stools, and worsening of systemic symptoms 4-Pruritus is often a major complaint of icteric patients Physical examination
1-Icteric sclera, skin, and secretions , 2- Mild weight loss of 2 to 5 kg , 3-Hepatomegaly Laboratory tests
1-Positive serum IgM anti-HAV
2-Mild elevations of serum bilirubin, γ-globulin, and hepatic transaminase (alanine transaminase [ALT], and aspartate transaminase [AST] values to about twice normal in acute anicteric disease
3 Elevations of alkaline phosphatase, γ -glutamyl transferase, and total bilirubin in patients with cholestatic illness

Diagnosis
Diagnosis of acute HAV infection depends on clinical suspicion, characteristic symptoms, elevated aminotransferases and bilirubin, and a positive anti-HAV IgM. The antibody peaks during the early phase of convalescence and remains positive for 4 to 6 months after the onset of the disease(1).
6-The minimal degree of liver cell damage with HAV is reflected by mild elevations of serum transaminases values to about twice normal.
Treatment (1).
1-Management of HAV infection is primarily supportive, including a healthy diet, rest, maintenance of fluid balance, avoidance of hepatotoxic drugs and alcohol.
2-Pharmacologic agents offer no clear benefit in the treatment of HAV.
Prevention
1-The spread of HAV can be best controlled by avoiding exposure. The most important measures to avoid exposure include good hand-washing techniques and good personal hygiene practices (1).
2-Vaccination :
Vaccination is recommended to groups at increased risk for HAV infections, such as for laboratory staff who work with the virus, some patients with haemophilia (1).
Hepatitis B
Hepatitis B is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.

Mode of Transmission :
A-Parenteral routes (e.g., needlestick injury, injection drug use, and transfusion)
B-Sexual contact C-Vertical or perinatal transmission (from mother to infant)
Clinical Course
1-The incubation period for HBV is 1 to 6 months
2-Hepatitis B may cause an acute viral hepatitis or chronic hepatitis .
3-The symptoms of acute infection with any hepatitis virus are similar (3) and include fever, anorexia, nausea, vomiting, jaundice, dark urine, clay-colored or pale stools, and abdominal pain (1).
4-Clinical manifestations of acute HBV infection are age dependent. Infants infected with HBV are generally asymptomatic, while about 85% to 95% of children aged 1 -to 5 years are asymptomatic (1).
Table 2. Clinical Presentation of Chronic Hepatitis B**
Signs and symptoms 1-Easy fatigability, anxiety, anorexia, and malaise . 2-Ascites, jaundice, variceal bleeding, and hepatic encephalopathy can manifest with liver decompensation 3-Hepatic encephalopathy is associated with hyperexcitability, impaired mentation, confusion, and eventually coma 4-Vomiting and seizures
Physical examination 1-Icteric sclera, skin, and secretions . 2-Spider angiomata

Laboratory tests 1-Presence of hepatitis B surface antigen for at least 6 months.
2-Intermittent elevations of hepatic transaminase (alanine transaminase [ALT] and aspartate transaminase [AST]) 3-Liver biopsies for pathologic classification as chronic persistent hepatitis, chronic active hepatitis, or cirrhosis
** Chronic hepatitis B can be present even without all the signs, symptoms, and physical examination findings listed being apparent.
5-Approximately 90% of infants but 10% of adolescents or adults develop chronic HBV. Chronic HBV predisposes patients to chronic liver disease, cirrhosis, and hepatocellular carcinoma (1).
6-The clinical presentation of chronic HBV is given in Table 2 (1).
Diagnosis
HBV virus contains a number of antigens that elicit a corresponding antibody response (2) :
A-Hepatitis B surface antigen (HBsAg) is detectable in serum in acute and chronic HBV infection and disappears after clearance of the virus.
B-Hepatitis B e antigen (HBeAg) appears shortly after HBsAg in the serum and its persistence is indicative of active viral replication and a high degree of infectivity.
C-The HBV viral DNA (HBV DNA) is the most accurate marker of viral replication. It is reported as copies per milliliter or International Units per milliliter..
D-Liver biopsy is useful to score the degree of inflammation and fibrosis in patients with chronic hepatitis
Treatment (1).
Goal of therapy
The key goal of therapy is to eradicate or permanently suppress HBV. The short-term goal is to limit hepatic inflammation and to reduce the risk of fibrosis. The long-term goal is to prevent transaminase flares and the development of complications, and to prolong survival (1). This expressed as (2) :
1-Clearance of HBV DNA.
2-HBeAg and HBsAg seroconversion (i.e., antigen disappearance and appearance of antibodies)
3-Normalization of liver enzymes.
4-Normalization of histology.
Acute Hepatitis B:
Treatment is supportive with monitoring fort acute liver failure which can occurs in less than 1 % of cases (4).
Chronic Hepatitis B:
Current treatment guidelines recommend treating patients with elevated ALT and high HBV DNA levels (5).
Current Treatment options are :
A-The interferons (IFN) ( IFN alfa-2a and IFN alfa-2b) :
Interferons are glycoproteins with antiviral, immunomodulatory, and antiproliferative actions. The addition of polyethylene glycol (PEG) to the standard IFN molecules (pegylation) results in prolonged half-life with improved bioavailability. IFN-alfa 2a and 2b is administered subcutaneously thrice weekly for 4-6 months, or peginterferon alfa for 48 weeks (2).
Conventional IFN is administered subcutaneously or intramuscularly daily or three times per week, and pegylated forms are administered once weekly(5)
HBeAg seroconversion is achieved in 30% of treated patients, and HBsAg seroconversion in 5%-10%. They do not induce resistant mutations (2).
In addition, many patients experience flare of liver disease during the administration of IFN alfa, and though this may be a marker of enhanced responsiveness to the therapy, many patients do not tolerate this drug-induced exacerbation of liver disease .Treatment with IFN is generally contraindicated in decompensated liver disease, since flares in these cases may precipitate overt liver failure (5).
Common adverse events from IFN therapy include flu-like syndrome (headache, fatigue, myalgias, arthralgias, fever, and chills), neuropsychiatric disorders (depression, irritability, and concentration impairment), reversible bone marrow suppression (neutropenia, thrombocytopenia, and anemia), and other effects (alopecia, thyroiditis, injection site reactions)(2).
B-Lamivudine is a nucleoside analog with antiviral activity. It is administered orally at 100 mg daily. Treatment success is proportional to treatment duration (2).
Advantages of lamivudine therapy include its low side-effect profile and its relatively low cost. The main disadvantage of lamivudine is the frequent emergence of viral resistance(5) (15%-20% per year of treatment)(2).Another disadvantage of lamivudine therapy is that optimal duration of therapy is unknown. The disadvantage of all oral agents for HBV infection, including lamivudine, is low rate of durability of response after the cessation of therapy (patients relapse after discontinuation of therapy in almost all cases)(5). C-Adefovir is a nucleotide analog with antiviral activity. It is administered orally at 10 mg daily. Treatment success is proportional to treatment duration. Adefovir can be used as a treatment option for patients with lamivudine resistance. It is safely used in patients with advanced or decompensated liver disease. 15-20 % of patients will develop resistance to adefovir after 4-5 years of treatment(2).
D-Entecavir is a nucleoside analog with antiviral activity. It is administered orally at 0.5 mg daily in patients not treated previously with nucleoside analogues and 1 mg daily in patients with known lamivudine resistance mutations. Resistant mutants are very rare in nucleoside-not treated patients. In lamivudine resistant patients, resistance mutations to entecavir are more frequent (2).
E-Telbivudine is a nucleoside analog. It was recently approved for treatment of HBV in the United States. Preliminary reports show robust ( عنيف, نشيط) antiviral activity with a mild to moderate rate of induction of resistant (2).
F-New agents, regimens, and combination therapies are currently under investigation (2).
Tenofovir is a reverse transcriptase inhibitor effective against HBV, including the lamivudine-resistant HBV. Recently published data suggest that tenofovir may be more potent than Adefovir (5).
G-Liver transplantation: For patients with end-stage liver disease due to chronic hepatitis B infection, transplantation is an option. To prevent reinfection of transplanted liver, hepatitis B immune globulin (HBIG) is administered immediately after transplantation. The addition of lamivudine to HBIG further reduces the reinfection rate . HBIG, however, is very expensive and substantially increases the cost of liver transplantation in patients with chronic hepatitis B infection (5).
Prevention :
1-Two products are available for prevention of hepatitis B infection: hepatitis B vaccine, which provides active immunity, and hepatitis B immune globulin (HBIG), which provides temporary passive immunity (1).
2- HBV vaccine should be considered for everyone, particularly in individuals with a history of multiple blood transfusions, patients on hemodialysis, health care workers, injection drug users, Infants born to HBsAg-positive mothers, ……………(2).
Hepatitis C Virus
Epidemiology
HCV is a global health problem with approximately 200 million carriers worldwide (2).
Modes of Transmission (2) .
1-Parenterally (e.g., transfusion, injection drug use, needlestick injury)
2-Sexually and from mother to offspring, although at a much lower frequency than HBV
Clinical Features
1-Patients with acute hepatitis C are often asymptomatic. The clinical course is generally mild with less than 25% of patients developing malaise, anorexia, and jaundice (1).
2-70% of cases eventually develop chronic hepatitis (1).
3-10-30% of patients with HCV infection develop cirrhosis (1). Progression to cirrhosis is slow (two to three decades) (2) and about 1% to 5% develop hepatocellular carcinoma (1).
Diagnosis
diagnosis is difficult as antibodies develop relatively late in the course of infection (5).
1-Antibodies against HCV (anti-HCV) may be undetectable for the first 8 weeks after infection. Positive tests are usually diagnostic in patients with elevated liver enzymes and with risk factors for the infection. (2).
2- HCV RNA can be detected in serum as early as 1-2 weeks after infection (2).
Treatment
Acute infection
IFN-alfa (standard or pegylated) for 6 months has been associated with a high rate of sustained HCV RNA clearance. The role of ribavirin in addition is under investigation (2).
Chronic infection :
A combination of SC pegylated-interferon (PEG-IFN) and oral nucleoside analogue ribavirin (2). The dosing regimen varies with the specific product and the duration of therapy varies with the product and HCV genotype ( or serotypes) (2).
Prevention:
1-No HCV vaccine is currently available.
2-Current recommendations for prevention of HCV include universal precautions for the prevention of blood-borne infections (1) .
Hepatitis D Virus
1-It is found throughout the world, and is endemic to the Mediterranean basin حَوْض, the Middle East, and portions of South America. Outside these areas, infections occur primarily in individuals who have received transfusions or in injection drug users. HDV requires the presence of HBV for infection and replication (2).
2-HDV infection clinically presents as:
A-Coinfection (acute hepatitis B and D).
B-Superinfection (chronic hepatitis B with acute hepatitis D).
C-Latent infection (e.g., in the liver transplant setting).
3-Diagnosis is made by finding HDV RNA or HDV antigen in serum or liver and by detecting antibody to the HDV antigen (2).
4-In patients with coinfection, the course is transient and self-limited. The rate of progression to chronicity is similar to the one reported for acute HBV. In superinfection, the HBV carriers may present with a severe acute hepatitis D exacerbation (2). such patient may eventually develop chronic infection of both type and eventually cirrhosis (4).
5-IFN-alfa is the treatment of choice for chronic hepatitis D (2).
6-Although there is no vaccine to prevent HDV in carriers of HBV, both infections can be prevented by timely administration of the HBV vaccine(2).
Hepatitis E Virus
1-Transmission closely resembles that of HAV (i.e., fecal-oral route) (2).
2-It differs from HAV in that infection during pregnancy is associated with the development of liver failure, which has high mortality rate (4) .
3-There is no chronic infection associated with HEV (2).
4-Treatment is supportive (2).
5-There is no pre- or postexposure prophylaxis (2).

References :
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, Sixth Edition. Copyright 2005, by The McGraw-Hill Companies, Inc.
2-Cooper, Daniel H.; Krainik, Andrew J.; Lubner, Sam J.; Reno, Hilary E. L. Washington Manual of Medical Therapeutics, The, 32nd Edition. Copyright 2007 . Published by Lippincott Williams & Wilkins.
3-Vanessa Sherwood. Viral hepatitis . Chemist &Druggist 26 February 2005. pages 21-24.
4-Nicholas A. B oon, Nicki R. Colledge and Brian R. Walker. Davidson's Principles and Pracrtice of Medicines . 23 th Edition 2006.
5-Jiwon Kim, Paula Phongsamran, and Jason Madison . Chronic Hepatitis B Infection . US Pharm. 2006;6:HS-5-HS-14.