Serologies     Workup    

There are at least six and likely more forms of viral hepatitis caused by six different viral agents. At least five can lead to acute hepatitis, but only three are currently understood to lead to chronic infection. These viruses are distinct and show no homology to structure, family, or replicative cycle.

     Hepatitis A: This is a small RNA virus that causes only an acute, self-limited infection. It is a member of the picornavirus, of which the poliovirus is a better known member. It is common worldwide, and is spread largely by the fecal-oral route. It has been the cause of many food-borne or water-borne epidemics worldwide. Symptoms of infection include nausea, vomiting, abdominal pain, scleral icterus, and jaundice. Infection is usually mild; however, it may be severe in adults. Associated laboratory abnormalities include transaminasemia and leukopenia. Resolution of symptoms and laboratory abnormalities followed by recurrence 2 to 18 weeks later is termed relapsing hepatitis A infection, and relapses may be multiple. Jaundice associated with hepatitis A infection may follow a prolonged course lasting 2 months or more.

Diagnosis is established by detecting IgM antibody to hepatitis A in the serum of afflicted individuals. False-negative results are not encountered. Serum IgM antibody usually becomes negative 3 months after infection. The presence of serum IgG antibodies is consistent with immunity. Recurrent infections may be diagnosed by demonstrating persistent shedding of virus in stool specimens.

Treatment is mostly supportive until symptoms of acute infection resolve. Pooled gamma globulin and immune serum globulin (ISG) are two methods to offer protection from infection with hepatitis A, especially when given prior to exposure. However, since hepatitis A vaccines are just as effective they have become the preferred intervention.

There are two vaccines currently available, and both (Havrix and Vaqta) are inactivated virus vaccines. The pediatric dose and adult dose are 0.5 ml and 1.0 ml, respectively, for both vaccines. Protection from infection lasting at least 7 years occurs when primary immunization is followed by a booster dose at 6 to 12 months. Vaccination should take place 4 weeks before travel to an endemic area is planned. If travel is planned to occur before 4 weeks has elapsed since vaccination, then treatment with immune globulin (0.02 ml/kg) should be administered at a different injection site. Persons who should be evaluated for the need for vaccination include the following: children (older than 2 years of age) who live in communities with high rates of infection from hepatitis A, homosexual men who are not immune, intravenous drug abusers, persons with chronic liver disease, persons receiving clotting factor concentrates, patients in whom chronic dialysis therapy is anticipated, travelers going to countries with a high infection rate, and persons with occupational risk factors.

     Hepatitis B: This is a DNA virus that belongs to the hepadnavirus family, and it is unique among the human race in its genome, antigenic structure, and replicative cycle. Hepatitis B can lead to chronic or acute infections, and it is a significant cause of morbidity and mortality worldwide. Infection may be acquired from infected organ transplants, as a sexually transmitted disease, from needle stick injuries, repeated intravenous drug abuse, and via the placenta. The strongest predictor of infectivity from needle sticks or of mother-to-fetus transmission is the presence of hepatitis B e antigen in the serum of the donor or mother. Persons from the Pacific rim have a high incidence of infection and should be screened accordingly as should patients who have been incarceraed or institutionalized. There is a 300-fold risk of developing hepatocellular carcinoma among chronic carriers. Routine vaccination for this infectious agent is now routinely practiced in many developed countries.

 Acute infection will be characterized by symptoms (anorexia, malaise, nausea/vomitimg, abdominal pain,scleral icteris, and jaundice) and a rapid and significant increase in the serum transaminases (often in excess of 1,000 IU/mL), which is sometimes associated with hyperbilirubinemia and hypoprothrombinemia. Diagnosis may be established via serologic testing. The HBsAg is usually the first abnormality noted and occurs approximately 4 weeks after infection. Next, IgM anti-HBc is noted. This usually appears 2 to 4 weeks after HBsAG is detected and persists much longer than HBsAG. It is for this reason that IgM anti-HBc can be used to diagnose acute hepatitis B infection in the absence of HBsAg, and this phase of infection is termed the window phase. Hypertransaminasemia persists for approximately 12 weeks. It is of interest to note that patients suffering from polyarteritis nodosa (PAN) also commonly test positive for HBsAG indicating hepatitis B as an etiologic agent. There is an increased incidence of PAN in areas where hepatitis B infection is endemic. Symptoms of hepatitis B infection, which include jaundice, malaise, fatigue, arthritis, right upper quadrant abdominal pain, nausea, vomiting, and anorexia, may persist for 8 to 10 weeks. Treatment for acute infection is entirely supportive with fluids, antiemetics, and pain control. Concomitant infection with the hepatitis delta virus should be ruled out in all cases of acute hepatitis B infection. Postexposure prophylaxis uses a combination of hepatitis B immune globulin and vaccination or vaccination alone without immune globulin.

Chronic hepatitis B infection is usually associated with a mild hypertransaminasemia, hypoprothrombinemia, and hypoalbuminemia. The diagnosis is confirmed by the continued presence of HBsAg in the serum of affected patients plus the presence of either HBV DNA or HBeAg. There are eight genotypes of HBV. The absence of HBsAg six months after acute infection excludes the diagnosis of chronic infection and no further testing is needed. There are four phases of chronic infection: immune tolerance (HBsAg +, HBeAg +, anti-HBeAb neg, HBV DNA>20,000IU/mL, normal ALT, minimal changes on liver biopsy); immune clearance (HBsAg +, HBeAg + anti HBeAb neg, HBV DNA >20,000IU/mL, elevated ALT, abnormal liver biopsy results); inactive carrier (HBsAg +, HBeAg neg, anti HBe Ab +, serum HBV DNA <2,000IU/mL, normal ALT, liver biopsy with minimal to no changes); and reactivation (HBsAg +, HBeAg neg, anti HBeAb +, HBV DNA levels >2,000IU/mL, elevated ALT levels, abnormal liver biopsy).  Patients in the immune clearance or reactivation phases (elevated ALT levels and abnormal biopsy results) are candidates for therapy with the ultimate goal being suppression of HBV DNA and Hep BsAg. A simplified approach to decide which patients may require therapy involves the HBV DNA level and the ALT level with >20,000 IU/mL being the cut off for high viral titers of DNA. If both levels are elevated treatment may be indicated. If both levels are low or normal then close follow-up may be adequate. If there is an elevation of one but not the other, then a liver biopsy is indicated to determine if therapy should be started. Patients should also be tested for the presence of concomitant hepatits A and C infections, the delta virus and HIV antibody if this was not done during the initial diagnosis. Chronic infection is a risk factor for the development of hepatocellular carcinoma (HCC), and infected persons should be screened for this malignancy with regular determination of the serum alpha feto-protein and ultrasound scanning of the liver. Unlike hepatitis C virus, cirrhosis need not be present for the patient to be at risk for HCC.

Options for therapy include Interferon alfa-2b, Peginterferon alfa-2a, Lamivudine, Adefovir, Entecavir, and Telbivudine. Entecavir and Telbivudine seem to have lower risks for recurrence. Consultation with a hepatologist may be prudent in the long term management of these patients.

Patients with HBV infection should be counseled to avoid alcohol, about means of disease transmission and their infectivity (safe sex, use of clean needles and disposal of dirty needles, placental transmission, etc.), to discontinue all possible hepatotoxic medications and to receive hepatitis A vaccination. All household and sexual contacts should be vaccinated if this has not been done already. Also, patients with infection should be counseled to abstain from donation of blood products, semen, and body organs.

Hepatitis C: This is an RNA virus. It leads to chronic infection in approximately 80% of cases, and leads to cirrhosis in about 25% of those with chronic infection and to hepatocellular carcinoma in a portion of those with cirrhosis. Factors associated with an increased risk for progression to cirrhosis include the following: continued alcohol consumption, obesity, age greater than 40 years at the time of infection, male sex, and diabetes mellitus. This virus is spread mostly by the parenteral route but can also be transmitted by maternal-infant exposure. As acute infection has few symptoms, most cases are chronic at the time of diagnosis. If the disease has not progressed to cirrhosis with its many symptoms, chronic hepatitis C infection is usually asymptomatic and is considered only when laboratory testing reveals mild persistent transaminasemia. Because hepatitis C generally causes an asymptomatic infection, persons with the following risk factors should be screened for infection regardless of transaminase levels: (1) history of receiving blood products before 1992 or clotting factor concentrates before 1987, (2) long-term hemodialysis patients, (3) persons with multiple sex partners, (4) close contacts of person with hepatitis C, (5) history of parental drug use, (6) sharing of instruments for intranasal drug use, (7) children born to HCV-positive mothers, or (8) persons with HIV infection.

Patients afflicted with chronic infection should be counseled regarding infectivity. Current recommendations include the following: (1) restrictions toward blood, organ, tissues, or semen donations; (2) engaging in safe sexual practices; (3) avoid sharing razors or toothbrushes; (4) abstaining from alcohol and hepatotoxic medications/drugs; and (5) instructing patients regarding modes of transmission and disposal of injection needles. It should be noted that transmission between sexual partners does occur but infrequently, and chronic monogamous partners need not use barrier protection. Patients with chronic infection and cirrhosis should be screened for hepatocellular carcinoma with serial alpha-feto protein determinations and ultrasound. Also, patients with chronic infection should receive the hepatitis A vaccine and should be consider for vaccination against hepatitis B depending on their risk factors and their immune status (patients with adequate HepB sAb titers are immune). Since therapies for hepatitis C are weight based and obesity is a risk factor for progressive hepatic fibrosis, patients should be encourage to lose as much weight as possible before initiating treatment in order to improve outcomes.

When the diagnosis is considered, screening with HCV antibody (HCV Ab) testing is the initial step. A positive result is then followed by HCV RNA testing (quantitative or qualitative). If the RNA test is positive (chronic HCV infection), then genotype testing should be performed to determine appropriate treatment. If the patient has HCV genotype 1, then quantitative testing should be done to determine the pretreatment viral load if the initial HCV RNA testing was qualitative. Patients who are immunocompromised may have a false-negative screening HCV Ab test and should be tested with HCV RNA testing. Patients suspected of acute HCV infection and infants less than one year of age born to HCV-positive women should be screened with HCV RNA testing and not HCV Ab testing.

Patients with genotypes 2 and 3 or low viral titers (<600,000 IU/mL) respond well to therapy, and patients infected with genotypes 2 or 3 may progress to treatment without a liver biopsy. Patients with genotype 1, high viral titers (>600,000 IU/mL), glucose intolerance, and persons of African heritage have a less favorable response to therapy. Liver biopsy is helpful in patients with genotype 1 infection as the presence of fibrosis, inflammation, or necrosis are indications to treat. Continued alcohol use/abuse, illicit drug abuse, and evidence of advanced cirrhosis are contraindications to therapy. Patients who manifest complications of hepatitis C virus infection to include cryoglobulinemia or glomerulonephritis should be considered for treatment regardless of the liver biopsy results in order to treat the underlying hepatitis C infection and thus the associated complication. 

Therapy for chronic infection includes interferon alpha plus weight based oral ribavirin (13 mg/kg/day). Treatment protocols include once weekly peg interferon alpha 2a (180 mcg/week subcutaneously) or 2b (either standard dose 1 mg/kg/week or high dose 1.5 mg/kg/week). Patients with infection due to genotypes 2 or 3 require only 24 weeks of therapy while patients with genotype 1 are treated for 48 weeks. Duration of therapy may be prolonged in cases where virilogic response to therapy is delayed and this decision is made on an individual cases basis. The protease inhibitors telaprevir or bocepravir may increase response rates but are not yet avalable. Factors associated with a good response to therapy include minimal baseline liver damage, low serum HCV RNA level (less than 600,000 IU/mL), and HCV genotypes other than type 1. A rapid virilogic response (RVR) to therapy within the first four weeks portends a better prognosis than a delayed virilogic response. A lack of virilogic response by week 12 is an indication to consider therapy cessation.  The goal of therapy is a sustained virilogic response (SVR) which is defined as being HCV RNA negative 24 weeks after finishing therapy. Patients who do not respond should be followed for progression towards cirrhosis and then undergo surveillance screening for hepatocellular carcinoma.

Hepatitis D: This is referred to as the delta virus, which is a small defective RNA virus that causes hepatitis only in individuals who are concurrently infected with the hepatitis B virus. When patients with hepatitis B, display a second, separate transaminasitis, coinfection with the delta virus should be suspected. Hepatitis D tends to be a severe disease with a high mortality rate in the acute disease and a propensity of the chronic form of disease to progress to cirrhosis. Hepatitis D is found endemically in some areas (Middle East, Amazon Basin) but in most areas of the world it is found largely in certain high risk groups, including parenteral drug abusers and recipients of multiple blood transfusions or plasma products. The delta virus can infect a person who is already a chronic carrier of HBV (superinfection) or it can be transmitted simultaneously with the HBV (co-infection). These two forms should be separated both because of the difference in prognosis and in patterns of serological events. Acute HDV coinfection is usually self-limited and rarely leads to chronic hepatitis. Acute HDV superinfection, on the other hand, often leads to fulminant or chronic hepatitis.

Diagnosis rests on finding anti-HDV antibody in the serum of a patient who is HBV-positive. In fact, all persons diagnosed with hepatitis B should be screened for delta hepatitis. Patients with concomitant delta virus infection should be referred to a specialist for management. Therapy is generally aimed at treating the underlying hepatitis B infection. Oral agents for hepatitis B are ineffective against delta virus. High dose peginterferon alfa-2b (1.5microg/kg/week) may clear hepatitis D infection in a percentage of patients resulting in a sustained response to therapy (undetectable HDV RNA PCR six months after cessation of therapy). Long term surveillance for progression towards cirrhosis or development of hepatocellular carcinoma is required.

Hepatitis E: This is a small RNA virus from the calicivirus family. It can only produce an acute viral infection. It does not lead to a chronic or carrier state. The transmission of this virus is by the fecal-oral route, and is often associated with food or water contamination. The virus was first identified from water-borne transmission in a retrospective study from two epidemics in India. In developed countries, infection with this virus is very rare and serological evaluation is not widely available.

Herpes Simplex Virus Infection Types 1 or 2: An estimated 20 to 25% of the adult population has serologic evidence of herpes simplex infection; however, resultant hepatitis is a rare complication. In cases of fulminant acute hepatic failure (transaminasemia and encephalopathy), it may be prudent to start intravenous acyclovir until the underlying etiology can be determined as fulminant liver failure secondary to HSV is an extremely fatal condition if not treated rapidly. If HSV is the cause, the patient may be changed to an oral antiviral (acyclovir, famciclovir, or valcyclovir) once their condition improves. The finding of vesicles on the skin of an involved patient is suggestive of the diagnosis but is not always present.  Liver histology from a biopsy specimen will reveal findings of focal necrosis with minimal surrounding inflammation, intranuclear inclusion bodies and the presence of viral antigens on immunohistochemical analysis.

Viral hepatitis may also occur with infections caused by the Epstein-Barr virus, cytomegalovirus, and human herpes virus-6 (HHV-6). A significant hepatitis may occur with EBV induce mononucleosis; however, this is usually transient and supportive care is all that is generally required.