Acute viral hepatitis: causes, symptoms, diagnosis, treatment

Acute viral hepatitis is a diffuse inflammation of the liver caused by specific hepatotropic viruses characterized by different routes of transmission and epidemiology. The nonspecific prodromal period of viral infection is accompanied by anorexia, nausea, often fever and pain in the right upper quadrant of the abdomen. Jaundice often develops, usually after other symptoms begin to disappear. In most cases, the infection resolves spontaneously, but sometimes progresses to chronic hepatitis. Rarely, acute viral hepatitis progresses to acute liver failure (fulminant hepatitis). Hygiene can prevent infection with acute viral hepatitis. Depending on the specificity of the virus, pre- and post-disease prophylaxis can be carried out by vaccination or the use of serum globulins. Treatment of acute viral hepatitis is usually symptomatic.

Acute viral hepatitis is a widespread and important disease worldwide, with various etiologies; each type of hepatitis has its own clinical, biochemical and morphological features. Liver infections caused by other viruses (e.g. Epstein-Barr virus, yellow fever virus, cytomegalovirus) are not called acute viral hepatitis at all.

[ 1 ]

What causes acute viral hepatitis?

At least five specific viruses cause acute viral hepatitis. Other, unknown viruses may also cause acute viral hepatitis.

Certain diseases or pathogens that cause liver inflammation

Diseases or pathogens	Manifestations
Viruses
Cytomegalovirus	In neonates: hepatomegaly, jaundice, congenital defects. In adults: mononucleosis-like illness with hepatitis; possible after blood transfusion
Epstein-Barr	Infectious mononucleosis. Clinical hepatitis with jaundice in 5-10%; subclinical liver damage in 90-95%. Acute hepatitis in the young (important)
Yellow fever	Jaundice with general intoxication, bleeding. Liver necrosis with a slight inflammatory reaction.
Other	Rarely hepatitis caused by herpes simplex, ECHO, Coxsackie, measles, rubella or chickenpox viruses
Bacteria
Actinomycosis	Granulomatous reaction of the liver with progressive necrotic abscesses
Pyogenic abscess	Severe infectious complication of portal pyemia and cholangitis; also possible hematogenous route or direct spread. Various microorganisms, especially gram-negative and anaerobic bacteria. Disease and intoxication, only moderate liver dysfunction. Differentiate from amebiasis
Tuberculosis	Liver is often involved. Granulomatous infiltration. Usually subclinical; rarely jaundice. Disproportionately elevated alkaline phosphatase
Other	Minor focal hepatitis in various systemic infections (frequent, usually subclinical)
Mushrooms
Histoplasmosis (Darling's disease)	Granulomas in the liver and spleen (usually subclinical), with subsequent calcification
Other	Granulomatous infiltration in cryptococcosis, coccidioidomycosis, blastomycosis and others
Protozoa
Amebiasis	Has important epidemiological significance, often without pronounced bowel disorder. Usually a single large abscess with melting. Enlarged, painful liver with moderate dysfunction. Differentiate from pyogenic abscess
Malaria	Hepatosplenomegaly in endemic areas (main cause). Jaundice absent or mild unless marked hemolysis
Toxoplasmosis	Transplacental infection. In neonates: jaundice, CNS damage and other systemic manifestations
Visceral leishmaniasis	Infiltration of the reticuloendothelial system by the parasite. Hepatosplenomegaly
Helminths
Ascariasis	Biliary obstruction by adults, granulomas in the parenchyma caused by larvae
Clonorchiasis	Biliary tract invasion; cholangitis, stones, cholangiocarcinoma
Echinococcosis	One or more hydatid cysts, usually with calcification at the periphery. Often asymptomatic; liver function is preserved. May be complicated by rupture into the peritoneal cavity or biliary tract
Fascioliasis	Acute: suggests hepatomegaly, fever, eosinophilia. Chronic: biliary fibrosis, cholangitis
Schistosomiasis	Periportal granulomatous reaction to eggs with progressive hepatosplenomegaly, pipestem fibrosis (Simmers fibrosis), portal hypertension, esophageal varices. Hepatocellular function is preserved; not true liver cirrhosis
Toxocariasis	Visceral larval migration syndrome. Hepatosplenomegaly with granulomas, eosinophilia
Spirochetes
Leptospirosis	Acute fever, prostration, jaundice, hemorrhage, renal failure. Liver necrosis (often moderate despite severe jaundice)
Syphilis	Congenital: neonatal hepatosplenomegaly, fibrosis. Acquired: variable course of hepatitis in the secondary stage, gummas with uneven scarring in the tertiary stage.
Relapsing fever	Borreliosis. General symptoms, hepatomegaly, sometimes jaundice
Unknown
Idiopathic granulomatous hepatitis	Active chronic granulomatous inflammation of unknown etiology (potypusarcoidosis). General symptoms (may dominate), fever, malaise
Sarcoidosis	Granulomatous infiltration (general signs, usually subclinical); rarely jaundice. Sometimes progressive inflammation with fibrosis, portal hypertension
Ulcerative colitis, Crohn's disease	Associated with liver disease, especially ulcerative colitis. Includes periportal inflammation (pericholangitis), sclerosing cholangitis, cholangiocarcinoma, autoimmune hepatitis. Little correlation with intestinal process activity or treatment

Viral hepatitis A (HAV)

Hepatitis A virus is a single-stranded RNA picornavirus. HAV infection is the most common cause of acute viral hepatitis, especially in children and adolescents. In some countries, more than 75% of adults are exposed to HAV, primarily through the feco-oral route of transmission, so this type of hepatitis occurs in areas of poor hygiene. Waterborne and foodborne transmission and epidemics are most common in underdeveloped countries. Occasionally, edible infected raw shellfish may be the source of infection. Sporadic cases also occur, usually as a result of human-to-human contact. The virus is excreted from the body in the feces before symptoms of acute viral hepatitis A develop, and this process usually ends several days after the onset of symptoms; thus, by the time hepatitis manifests clinically, the virus is no longer infective. Chronic carriage of HAV has not been described; hepatitis does not become chronic and does not progress to cirrhosis.

Viral hepatitis B (HBV)

Hepatitis B virus is a complex and best characterized hepatitis virus. The infectious particle consists of a viral core and an outer surface membrane. The core contains a circular double helix of DNA and DNA polymerase, and replication occurs in the nucleus of the infected hepatocyte. The surface membrane is formed in the cytoplasm, for unknown reasons in great excess.

HBV is the second most common cause of acute viral hepatitis. Undiagnosed infections are common but much less common than HAV infections. Hepatitis B virus infection is most often transmitted parenterally, usually through contaminated blood or blood products. Routine screening of donor blood for hepatitis B (HBsAg) has virtually eliminated transmission by blood transfusion, but needle sharing during drug use remains a risk. The risk of HBV infection is increased among patients in hemodialysis and oncology units and among hospital personnel who come into contact with blood. Non-parenteral transmission occurs through sexual contact (heterosexual and homosexual) and in closed settings such as psychiatric hospitals and prisons, but the infectivity of this virus is much lower than that of HAV and the route of transmission is often unknown. The role of insect bites in transmission is unclear. In many cases, acute hepatitis B occurs sporadically from an unknown source.

For unknown reasons, HBV is sometimes associated primarily with certain extrahepatic manifestations, including polyarteritis nodosa and other connective tissue diseases, membranous glomerulonephritis, and idiopathic mixed cryoglobulinemia. The pathogenic role of HBV in these diseases is unclear, but autoimmune mechanisms have been suggested.

Chronic HBV carriers constitute a worldwide reservoir of infection. Prevalence varies widely and depends on a number of factors, including geographic areas (e.g., less than 0.5% in North America and Northern Europe, more than 10% in some regions of the Far East). Direct mother-to-child transmission of the virus is common.

Viral hepatitis C (HCV)

Hepatitis C virus (HCV) is a single-stranded RNA virus belonging to the flavivirus family. There are six major HCV subtypes that differ in their amino acid sequence (genotypes); these subtypes vary by geographic location, virulence, and response to therapy. HCV can also change its amino acid structure over time within an infected patient (quasispecies).

Infection is usually transmitted through blood, primarily by sharing intravenous needles among drug users, but also through tattooing and body piercing. Transmission by sexual contact and direct mother-to-child transmission are relatively rare. Transmission by blood transfusion has become very rare since the introduction of screening of donor blood. Some sporadic cases occur in patients with no obvious risk factors. The prevalence of HCV varies with geography and other risk factors.

Hepatitis C virus infection is sometimes associated with specific systemic diseases, including idiopathic mixed cryoglobulinemia, porphyria cutanea tarda (approximately 60-80% of patients with porphyria have HCV, but only some patients with hepatitis C virus develop porphyria), and glomerulonephritis; the mechanisms are unclear. In addition, hepatitis C virus infection is found in 20% of patients with alcoholic liver disease. The reasons for this high association are unclear, since drug abuse and alcoholism are only occasionally present. In these patients, hepatitis C virus and alcohol act synergistically, increasing liver damage.

Hepatitis D Virus (HDV)

Hepatitis D virus, or delta factor, is a defective RNA virus that can only replicate in the presence of HBV. It is rarely seen as a coinfection with acute hepatitis B or as a superinfection in chronic hepatitis B. The affected hepatocyte contains delta particles coated with HBsAg. The prevalence of HDV varies widely by geographic region, with localized endemic foci existing in some countries. Intravenous drug users are a relatively high-risk group, but unlike HBV, HDV is not prevalent among homosexuals.

Viral hepatitis E (HEV)

Viral hepatitis E is an RNA-containing virus with an enteral route of transmission. Outbreaks of acute hepatitis E have been reported in China, India, Mexico, Pakistan, Peru, Russia, central and northern Africa and are caused by the virus entering water with sewage. These outbreaks have epidemiological features similar to HAV epidemics. Sporadic cases are also observed. No outbreaks have been reported in the United States or Western Europe. Like hepatitis A, HEV does not cause chronic hepatitis or liver cirrhosis; chronic carriage is absent.

Symptoms of acute viral hepatitis

Acute infection has predictable phases of development. Acute viral hepatitis begins with an incubation period during which the virus multiplies and spreads asymptomatically. The prodromal, or preicteric, phase has nonspecific symptoms of acute viral hepatitis, such as severe anorexia, malaise, nausea and vomiting, often fever and pain in the right upper quadrant of the abdomen, sometimes urticaria and arthralgia, especially in HBV infection. After 3-10 days, the urine darkens, jaundice occurs (icteric phase). General symptoms of acute viral hepatitis often regress, the patient's well-being improves despite progressive jaundice. During the icteric phase, the liver is usually enlarged and painful, but the liver edge remains soft and smooth. Moderate splenomegaly is observed in 15-20% of patients. Jaundice usually peaks between the first and second weeks and then disappears within 2 to 4 weeks (recovery phase). Appetite is restored after the first week. Acute viral hepatitis usually resolves spontaneously after 4 to 8 weeks.

Sometimes acute viral hepatitis occurs as a flu-like illness without jaundice, which is the only manifestation of the infection. This is more common than hepatitis with jaundice in HCV infection and in children with HAV infection.

Some patients may experience recurrent hepatitis, characterized by recurrence of symptoms during the recovery phase. Manifestations of cholestasis may develop during the icteric phase (cholestatic hepatitis), but they usually resolve. In the case of persistent hepatitis, despite general regression of inflammation, jaundice may persist for a long time, leading to an increase in the level of alkaline phosphatase and the appearance of skin itching.

HAV often does not cause jaundice and has no symptoms. It almost invariably resolves after acute infection, although early relapse may occur.

HBV causes a wide spectrum of liver disease, from subclinical carriage to severe or fulminant acute hepatitis, especially in the elderly, in whom mortality can reach 10-15%. Chronic HBV infection may eventually progress to hepatocellular carcinoma, even without prior cirrhosis.

Hepatitis C virus infection may be asymptomatic during the acute phase of infection. Severity often fluctuates, with exacerbations of hepatitis and fluctuating increases in aminotransferase levels over years or even decades. HCV has the highest risk of progression to chronicity (approximately 75%). Chronic hepatitis is usually asymptomatic or has few or no symptoms, but always progresses to cirrhosis in 20–30% of patients; cirrhosis often takes decades to manifest. Hepatocellular carcinoma may result from HCV-induced cirrhosis and is very rare as a result of chronic infection without cirrhosis (unlike HBV infection).

Acute HDV infection usually occurs as an unusually severe acute HBV infection (coinfection), as an exacerbation of chronic HBV carriage (superinfection), or as a relatively aggressive chronic HBV infection.

HEV can be severe, especially in pregnant women.

Diagnosis of acute viral hepatitis

In the prodromal period, acute viral hepatitis resembles various non-specific viral diseases, which is why the diagnosis of acute viral hepatitis is difficult. In patients without jaundice and in case of suspected hepatitis in the presence of risk factors, non-specific functional liver tests are first examined, including aminotransferases, bilirubin and alkaline phosphatase. Usually, the suspicion of acute hepatitis arises only in the icteric period. Therefore, differential diagnosis of acute viral hepatitis from other diseases causing jaundice is necessary.

As a rule, acute viral hepatitis is differentiated from other causes of jaundice by the increase in AST and ALT (usually > 400 IU/L). The ALT level is usually higher than the AST level, but there is almost no absolute correlation between enzyme levels and the severity of the clinical course. Enzyme levels increase early in the prodromal phase, the peak of increase precedes the maximum manifestation of jaundice, and a decrease occurs slowly during the recovery period. Bilirubin in the urine usually precedes jaundice. Hyperbilirubinemia in acute viral hepatitis can be expressed to varying degrees, the determination of bilirubin fractions has no clinical value. Alkaline phosphatase is usually moderately increased; its significant increase may indicate extrahepatic cholestasis and requires instrumental examination (eg, ultrasound). Liver biopsy is generally not required unless the diagnosis is in doubt. If laboratory test results suggest acute hepatitis, especially if ALT and AST are > 1000 IU/L, INR is tested. Manifestation of portosystemic encephalopathy, hemorrhagic diathesis, and prolongation of INR indicate fulminant hepatitis.

If acute viral hepatitis is suspected, its etiology must be verified. History taking may be the only way to diagnose drug-induced or toxic hepatitis. History should also identify risk factors for viral hepatitis. Prodromal sore throat and diffuse adenopathy may suggest infectious mononucleosis rather than viral hepatitis. Alcoholic hepatitis requires a history of alcohol abuse, gradual onset of symptoms, and the presence of spider veins or signs of chronic alcohol abuse or chronic liver disease. Aminotransferase levels rarely exceed 300 IU/L, even in severe cases. In addition, unlike in alcoholic liver disease, ALT is usually higher than AST in viral hepatitis, although this is not a reliable differential diagnosis. In doubtful cases, liver biopsy helps to differentiate alcoholic from viral hepatitis.

Patients with suspected viral hepatitis should undergo the following tests to identify hepatitis A, B, or C virus: anti-HAV IgM, HBsAg, IgM to hepatitis B core antigen (anti-HBc IgM), and anti-HCV. If some of these are positive, further serologic testing may be required to differentiate acute hepatitis from previous or chronic infection. If serology suggests hepatitis B, hepatitis B e antigen (HBeAg) and anti-HBe testing are usually performed to more accurately predict the course of the disease and initiate antiviral therapy. In severe cases of serologically confirmed HBV, anti-HDV testing is performed. If the patient has recently been in an endemic focus, anti-HEV IgM testing should be performed.

HAV is present in the serum only during acute infection and is not detectable by known clinical tests. IgM antibodies usually appear early in the course of infection and peak in titer approximately 1–2 weeks after the onset of jaundice, gradually declining over several weeks; this is followed by the appearance of protective IgG antibodies (anti-HAV), which usually persist for life. Thus, IgM is a marker of acute infection, whereas anti-HAV IgG simply indicates past HAV and immunity to the infection.

[ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ]

Serological diagnostics of hepatitis A

	HAV	Transferred HAV
Anti-HAV IgM	+	-
Anti-HAV IgG	-	+

HAV - hepatitis A virus. Previous infectious HAV.

Serological diagnostics of hepatitis B

	HBV	Chronic	Transferred2
HBsAg	+	+	-
Anti-HBs	-	-	+
Anti-HBc IgM	+	-	-
Anti-NVs IgG	-	+	+
HBeAg	+	+	-
Anti-NVE	-	+	+
HBV DNA	+	+	-

HBV - hepatitis B virus; HBsAg - hepatitis B virus surface antigen; HBcAg - hepatitis B virus core antigen; HBeAg - hepatitis B virus e-antigen.

Anti-HBV antibody levels should be determined when serologically confirming the presence of HBV in severe infection.

² Previous HBV infection with recovery.

Anti-HBs is also considered as the only serological marker after HBV vaccination.

Serological diagnostics of hepatitis C

	Spicy	Chronic	Post-HCV
Anti-HCV	+	+	+
HCV RNA	+	+	-

HCV - hepatitis C virus. Past HCV infection with spontaneous recovery or effective therapy.

Acute viral hepatitis B has at least three different antigen-antibody systems that can be tested: HBsAg, HBeAg, and HBeAg. Viral DNA (HBV DNA) can also be tested. The HBV surface antigen, i.e., HBsAg, can be detected in serum. HBsAg usually appears during the incubation period, usually 1-6 weeks before the onset of clinical symptoms or changes in biochemical tests, and indicates the presence of viremia, which disappears during recovery. However, the presence of HBsAg is sometimes transient. The corresponding protective antibodies (anti-HBs) appear weeks to months after clinical recovery and usually persist for life; thus, its detection indicates past HBV infection and immunity. In 5-10% of patients, HBsAg persists and antibodies are not produced: these patients become asymptomatic carriers of the virus or subsequently develop chronic hepatitis.

HBsAg is a core antigen of the virus. Without the use of special methods, it is detected only in affected liver cells, but not in the blood serum. Antibodies to HBsAg (anti-HBc) usually appear at the beginning of the clinical phase of the disease; subsequently, antibody titers gradually decrease over several years or throughout life. Their presence along with anti-HBs indicates recovery from past HBV infection. Anti-HBc antibodies are also present in chronic HBsAg carriers who do not give an anti-HBs response. In acute infection, anti-HBc is represented mainly by immunoglobulins of the IgM class, whereas in chronic infection, anti-HBc IgG predominates. Anti-HBc IgM are sensitive markers of acute HBV infection, and in some cases are the only markers of recent infection in the period between the disappearance of HBsAg and the appearance of anti-HBs.

HBeAg is a protein of the viral core (not to be confused with the hepatitis E virus) that appears only in the presence of HBsAg in the serum. HBeAg suggests active replication and high infectivity of the virus. In contrast, the presence of the corresponding antibody (anti-HBe) suggests lower infectivity. Thus, the e-antigen is more informative as a prognostic marker than for diagnosis. Chronic liver disease develops more frequently among patients with HBeAg and less frequently among patients with anti-HBe.

In patients with active HBV infection, viral DNA (HBV DNA) can be detected in serum by special testing, but this test is not always available.

In HCV, serum antibodies (anti-HCV) almost always indicate active infection; they are not protective. Anti-HCV usually appears within 2 weeks of acute infection, but sometimes at a later date. In a small percentage of patients, anti-HCV simply reflects previous exposure to the virus with spontaneous clearance, rather than the presence of active infection. ALT and AST levels are normal. In unclear cases, quantitative HCV RNA testing is performed.

In HDVaHTH-HDV indicate active infection. They may not be detected for several weeks after the onset of acute illness.

In HEV, anti-HEV IgM is not detectable by conventional methods. In patients with an endemic history, in combination with clinical data, the presence of anti-HEV indicates acute HEV infection.

If biopsy is performed, a similar histopathologic picture is usually seen regardless of the specificity of the virus: acidophilic hepatocellular necrosis, mononuclear inflammatory infiltrates, histologic signs of regeneration. HBV can sometimes be diagnosed by the presence of a ground-glass opacity (due to the filling of the cytoplasm with HBsAg) and by special immunostaining techniques for viral components. However, these signs are not characteristic of acute HBV and are much more typical of chronic HBV infection. Identification of HCV as an etiologic factor is sometimes possible on the basis of subtle morphologic features. Liver biopsy helps in the prognosis of acute hepatitis, but is rarely performed solely for this purpose. Complete histologic recovery occurs unless extensive necrosis connecting all the acini (bridging necrosis) occurs. Most patients with bridging necrosis recover completely. However, in some cases the process progresses to chronic hepatitis.

Treatment of acute viral hepatitis

No treatment for acute viral hepatitis alters the course of the disease, except in selected cases where effective post-exposure immunoprophylaxis is indicated. Alcohol, which increases liver injury, should be avoided. Dietary or activity restrictions, including the commonly prescribed bed rest, have no scientific basis. Most patients can safely return to work after resolution of jaundice, even if AST or ALT levels are slightly elevated. In cholestatic hepatitis, cholestyramine 8 g orally once or twice daily may reduce pruritus. A case of viral hepatitis should be reported to the local or city health department.

Prevention of acute viral hepatitis

Because treatment effectiveness is limited, prevention of acute viral hepatitis is essential. Personal hygiene can prevent transmission, especially feco-oral transmission, as seen with HAV and HEV. Blood and other body fluids (eg, saliva, semen) from patients with acute HBV and HCV and stool from patients with HAV are considered infectious. Barrier measures to infection are recommended, but patient isolation is of little value in preventing the spread of HAV and of none at all for HBV or HCV infections. The incidence of post-transfusion infections is minimized by avoiding unnecessary transfusions and by testing all donors for HBsAg and anti-HCV. Screening of donors has reduced the incidence of post-transfusion infections to 1/100,000 units of blood components transfused.

Immunoprophylaxis may include active immunization using vaccines and passive immunization.

Prevention of acute viral hepatitis A

Pre-exposure prophylaxis of HAV infection should be provided to people traveling to highly endemic areas. It should also be given to military personnel, day care workers, and diagnostic laboratory workers, as well as to patients with chronic liver disease due to the increased risk of fulminant hepatitis A. Several HAV vaccines with different doses and schedules have been developed; they are safe, provide protection for approximately 4 weeks, and provide prolonged protection (possibly more than 20 years).

Standard immune globulin, formerly called serum immune globulin, prevents or reduces the severity of HAV infection and is used for post-exposure prophylaxis; 0.02 ml/kg intramuscularly is usually recommended, but some authorities suggest increasing the dose to 0.06 ml/kg (3 ml to 5 ml for adults).

Prevention of acute viral hepatitis B

Vaccination in endemic areas has dramatically reduced the prevalence of infection. Preexposure immunization has long been recommended for high-risk individuals. However, selective vaccination of high-risk groups in the United States and other nonendemic areas has not significantly reduced the incidence of hepatitis B virus infection; therefore, vaccination is now recommended for all Americans under age 18, beginning at birth. Universal vaccination in all countries is desirable, but it is too expensive and therefore unrealistic.

Two recombinant vaccines have been developed; they are safe, even during pregnancy. The vaccination regimen includes three intramuscular injections into the deltoid muscle - primary immunization and a booster dose at 1 month and 6 months. Children are given lower doses, and patients receiving immunosuppressive therapy or undergoing hemodialysis are given higher doses.

After vaccination, the protective level of anti-HBs persists for up to 5 years in 80-90% and up to 10 years in 60-80% of vaccinated individuals. Booster immunizations are recommended for patients undergoing hemodialysis or receiving immunosuppressive drugs whose anti-HBs is less than 10 mIU/ml.

Postexposure immunoprophylaxis of HBV infection combines vaccination with the administration of hepatitis B immunoglobulin (HBIG), a preparation with a high titer of anti-HBs. Apparently, HBIG does not prevent the development of infection, but prevents or reduces clinical manifestations of the disease. Newborns of HBsAg-positive mothers are given an initial dose of vaccine and 0.5 ml of HBIG intramuscularly in the thigh immediately after birth. Within a few days after sexual contact with an HBsAg-positive partner or contact of damaged skin or mucous membrane with HBsAg-positive blood, 0.06 ml/kg of HBIG should be administered intramuscularly along with the vaccine. A previously vaccinated patient should be tested for the presence of anti-HBs after percutaneous exposure to HBsAg-positive blood; if titers are less than 10 mIU/ml, a booster vaccination is performed.

Prevention of acute viral hepatitis C, D, E

There are currently no drugs for immunoprophylaxis of HDV, HCV, or HEV infections. However, prophylaxis of acute viral hepatitis B prevents acute viral hepatitis D. The development of a vaccine against HCV infection is difficult due to the marked variability of the viral genome.