Tuesday, February 26, 2013

Viral Hepatitis: It's clinical Manifestation And Importance




Acute hepatite can occur or be mimicked in a variety of infectious diseases (cytomegalovirus, Epstein-Barr virus, toxoplasmosis, rubella, scarlet fever, secondary syphilis, salmonellosis, amoebic liver abscess and malaria) in which the liver is not the primary target of infection. Viral infection is the most frequent cause of hepatite in patients, younger than 14 years old. The prophylaxis and treatment of hepatite depends on the identity of the viral etiology.

HEPATITIS A THROUGH E

DEFINITION. Viral hepatitis is a major health problem in developing and developed countries. Recent advances in the field of molecular biology have aided identification and understanding of the pathogenesis of the five viruses that are now known to cause hepatitis as their primary disease manifestation. These hepatotropic viruses are designated hepatitis A, B, C, D, and E. Many other viruses can cause hepatitis as part of their clinical spectrum including herpes simplex, cytomegalovirus, Epstein-Barr, varicella, human immunodeficiency, adenovirus enteroviruses, and arboviruses. Hepatic involvement with these viruses is usually only one component of a multisystem disease.

The five hepatitis viruses are a heterogenous group of viruses that cause similar acute clinical illness. Hepatitis A, C, D, and E are RNA viruses representing four different families, and hepatitis B is a DNA virus.

Hepatitis A and E are not known to cause chronic illness, whereas hepatitis B, C, and D cause important morbidity and mortality through chronic infections. In the United States, hepatitis A virus (HAV) appears to cause most cases of hepatitis in children. Hepatitis B probably accounts for about one third of cases in children, whereas hepatitis C is found in approximately 20%. Hepatitis D occurs in only a small percentage of children who must also have active hepatitis B virus (HBV) infection. Hepatitis E has not been reported in children who have lived and traveled only in the United States.

HEPATITIS A
 
ETIOLOGY. HAV is a 27-nm diameter, RNA-containing virus that is a member of the Picornavirus family. It was isolated originally from stools of infected patients. Laboratory strains of HAV have been propagated in tissue culture. Acute infection is diagnosed by detecting immunoglobulin (Ig)M (IgM) antibodies (anti-HAV) by radioimmunoassay or, rarely, by identifying viral particles in stool.

EPIDEMIOLOGY. HAV infections occur throughout the world but are most common in developing countries, where the prevalence rate approaches 100% in children by the age of 5 yr. In the United States, approximately 30% of the adult population have evidence for previous HAV infection; the rates of infection are similar in the 1st, 2nd, and 3rd decades of life. Hepatitis A causes only acute hepatitis. The illness is much more likely to be symptomatic in adults; most infections in children younger than 5 yr are asymptomatic or have mild, nonspecific manifestations. The transmission of HAV is almost always by person-to-person contact. Spread is predominantly by the fecal-oral route; percutaneous transmission is a rare occurrence and maternal-neonatal transmission is not recognized as an epidemiologic entity. HAV infection during pregnancy or at the time of delivery does not appear to result in complications of pregnancy or clinical disease in the newborn. The infectivity of human saliva, urine, and semen is unknown. In the United States, increased risk of infection is found in households, day-care centers, household contacts of children in day-care centers, and homosexual populations. Common-source foodborne and waterborne outbreaks have occurred, including several resulting from contaminated shellfish. Fecal excretion of the virus occurs late in the incubation period, reaches its peak just before the onset of symptoms, and is minimal in the week after the onset of jaundice. The mean incubation period for HAV is about 4 wk.

PATHOLOGY.

The acute response of the liver to HAV is similar to that of the other four hepatitis viruses. The entire liver is involved with necrosis, most marked in the centrilobular areas, and increased cellularity, which is predominant in the portal areas. The lobular architecture remains intact, although balloon degeneration and necrosis of parenchymal cells occur initially. Fatty change is rare. A diffuse mononuclear cell inflammatory reaction causes expansion in the portal tracts; bile duct proliferation is common, but bile duct damage is not often found. Diffuse Kupffer cell hyperplasia is present in the sinusoids along with infiltration of polymorphonuclear leukocytes and eosinophils. Neonates respond to hepatic injury by forming giant cells. In fulminant hepatitis, total destruction of the parenchyma occurs, leaving only connective tissue septa. By 3 months after the onset of acute hepatitis resulting from HAV, the liver usually is normal morphologically.
Hepatocyte

Other organ systems can be affected during HAV infection. Regional lymph nodes and the spleen may be enlarged. The bone marrow may be moderately hypoplastic, and aplastic anemia has been reported. Small-intestine tissue may show changes in villous structure, and ulceration of the gastrointestinal tract can occur, especially in fatal cases. Acute pancreatitis and myocarditis have been reported rarely, and renal, joint, and skin involvement may result from circulating immune complexes.

PATHOGENESIS.

Injury in acute hepatitis is caused by several mechanisms. The initial injury in hepatitis A is thought to be cytopathic. Regardless of the mechanism of initial injury to the liver, damage from the five hepatitis viruses is evident in three main ways. The first is a reflection of injury to the hepatocytes, which release alanine aminotransferase (ALT, formerly serum glutamate pyruvate transaminase) and aspartate aminotransferase (AST, formerly serum glutamic-oxaloacetic transaminase) into the bloodstream. The ALT is more specific to the liver than the AST, which also can be elevated after injury to erythrocytes, skeletal muscle, or myocardial cells. The height of elevation does not correlate with the extent of hepatocellular necrosis and has little prognostic value. In some cases, a falling aminotransferase level may predict a poor outcome if the decline occurs in conjunction with a rising bilirubin and prolonged prothrombin time (PT). This combination of findings indicates that massive hepatic injury has occurred, resulting in few functioning hepatocytes. Another enzyme, lactate dehydrogenase is even less specific to liver than AST and usually is not helpful in evaluating liver injury. Viral hepatitis is also associated with cholestatic jaundice, in which both direct and indirect bilirubin levels are elevated. Jaundice results from obstruction of biliary flow and damage to hepatocytes. Elevations of serum alkaline phosphatase, 5-nucleotidase, g-glutamyl transpeptidase, and urobilinogen all can reflect injury to the biliary system. Abnormal protein synthesis by hepatocytes is reflected by increased PT. Because of the short half-life of these proteins, the PT is a sensitive indicator of damage to the liver. Serum albumin is another liver-manufactured serum protein, but its longer half-life limits its relevance for monitoring acute liver injury. Cholestasis results in a decreased intestinal bile acid pool and decreased absorption of fat-soluble vitamins. Hepatic injury also may result in changes in carbohydrate, ammonia, and drug metabolism.

CLINICAL MANIFESTATIONS.

The onset of HAV infection usually is abrupt and is accompanied by systemic complaints of fever, malaise, nausea, emesis, anorexia, and abdominal discomfort. This prodrome may be mild and often goes unnoticed in infants and preschool-age children. Diarrhea often occurs in children, but constipation is more common in adults. Jaundice may be so subtle in young children that it can be detected only by laboratory tests. When they occur, jaundice and dark urine usually develop after the systemic symptoms. In contrast to HAV infections in children, most HAV infections in adults are symptomatic and can be severe. Symptoms of HAV infection include right upper quadrant pain, dark-colored urine, and jaundice. The duration of symptoms usually is less than 1 mo, and appetite, exercise tolerance, and a feeling of well-being gradually return. Almost all patients with HAV infection will recover completely, but a relapsing course can occur for several months. Fulminant hepatitis leading to death is rare, and chronic infection does not occur.

DIAGNOSIS. The diagnosis of HAV infection should be considered when a history of jaundice exists in family contacts, friends, schoolmates, day-care playmates, or school personnel or if the child or family has traveled to an endemic area. The diagnosis is made by serologic criteria; liver biopsies rarely are performed. Anti-HAV is detected at the onset of symptoms of acute hepatitis A and persists for life. The acute infection is diagnosed by the presence of IgM anti-HAV, which can be detected for 3–12 mo; thereafter, IgG anti-HAV is found. The virus is excreted in stools from 2 wk before to 1 wk after the onset of illness. Rises are almost universally found in ALT, AST, bilirubin, alkaline phosphatase 5´-nucleotidase, and g-glutamyl transpeptidase and do not help to differentiate the cause. The PT should always be measured in a child with hepatitis to help assess the extent of liver injury; prolongation is a serious sign mandating hospitalization.

DIFFERENTIAL DIAGNOSIS.

 The possible causes of hepatitis vary somewhat by age. Physiologic jaundice, hemolytic disease, and sepsis in neonates usually are distinguished easily from hepatitis. After the immediate newborn period, infection remains an important cause of hyperbilirubinemia, but metabolic and anatomic causes (biliary atresia and choledochal cysts) also must be considered. The introduction of pigmented vegetables into the infant's diet may result in carotenemia, which may be mistaken for jaundice.

In later infancy and childhood, hemolytic-uremic syndrome may be mistaken initially for hepatitis. Reye and Reye-like syndromes present in a similar fashion to acute fulminating hepatitis. Jaundice also may occur with malaria, leptospirosis, and brucellosis and with severe infection in older children, particularly in those with malignant disorders or with immunodeficiency. Gallstones may obstruct biliary drainage and cause jaundice in adolescents as well as in children with chronic hemolytic processes. Hepatitis may be the initial presentation of Wilson disease, cystic fibrosis, a-1-antitrypsin deficiency, and Jamaican vomiting sickness. The liver may be involved in collagen vascular diseases including systemic lupus erythematosus.

Medications, including acetaminophen overdose, valproic acid, and various hepatotoxins, can be associated with a hepatitis-like picture. Drugs well tolerated in healthy children may cause hepatic dysfunction in children with certain illnesses.

COMPLICATIONS.

Children almost always recover from HAV infection. Rarely, fulminant hepatitis can occur, in which a progressive rise in serum bilirubin is accompanied by an initial rise in aminotransferases followed by a fall to normal or low values. Hepatic synthetic function decreases and the PT becomes prolonged, often accompanied by bleeding. The serum albumin falls, causing edema and ascites. The ammonia usually rises and the sensorium becomes altered, progressing from drowsiness to stupor and then deep coma. Progression to end-stage disease and death can occur in less than 1 wk, or can develop more insidiously.

PREVENTION. The recent development of highly immunogenic and safe formalin-killed vaccines marks a major advance in the prevention of hepatitis A. Vaccination of young children in endemic areas is unnecessary because the disease is almost always asymptomatic or mild and confers lifelong immunity. In industrialized countries, vaccination of high-risk children may be of benefit because these children can become carriers of the disease and could infect older siblings and parents who are at greater risk for more severe disease. Vaccination will be of special value to unexposed travelers from developed countries when they travel to hepatitis A–endemic areas.

Enteric precautions should be observed for hospitalized, infected patients who are incontinent of stool or who are in diapers. Careful hand washing is necessary, particularly after changing diapers and before preparing or serving food. Persons infected with HAV are contagious for about 1 wk after onset of jaundice. There is no need to isolate older, continent children, but their stools and fecally contaminated materials should be treated with precautions, and strict hand washing should be practiced.

Standard pooled Ig is effective in modifying clinical manifestations of HAV infection. The prophylactic value is greatest when given early in the incubation period and declines thereafter. Ig is recommended for all susceptible individuals traveling to developing countries. Unimmunized household contacts should receive a single intramuscular dose of Ig as soon as possible after exposure. This is effective in preventing clinical hepatitis, although infection may still occur. Giving Ig more than 2 wk after exposure is not indicated.

Ig is not recommended routinely for sporadic, nonhousehold exposures (e.g., protection of hospital personnel or schoolmates). Mass administration of Ig to schoolchildren has been used when epidemics have been school centered. When HAV occurs in a child-care center with children not yet toilet trained, Ig should be administered to all children and personnel. It also is advisable to administer Ig to family members of children in diapers.

 HEPATITIS B

 ETIOLOGY.
HBV is a 42-nm diameter member of the hepadnavirus family, a noncytopathogenic, hepatotropic group of DNA viruses. HBV has a circular, partially double-stranded DNA genome composed of approximately 3,200 nucleotides. Four genes have been identified: the S, C, X, and P genes. The surface of the virus includes two particles designated hepatitis B surface antigen (HBsAg): a 22-nm diameter spherical particle and a 22-nm wide tubular particle with a variable length of up to 200 nm. The inner portion of the virion contains hepatitis B core antigen (HBcAg) and a nonstructural antigen called hepatitis B e antigen (HBeAg), a nonparticulate–soluble antigen derived from HBcAg by proteolytic self-cleavage. Replication of HBV occurs predominantly in the liver but also occurs in lymphocytes, spleen, kidney, and pancreas.


EPIDEMIOLOGY. Worldwide, the areas of highest prevalence of HBV infection are subSaharan Africa, China, parts of the middle East, the Amazon basin, and the PacificIslands. In the United States, the Eskimo population in Alaska has the highest prevalence rate. An estimated 300,000 new cases of HBV infection occur in the United States each year, with the 20- to 39-yr age group at greatest risk. The number of new cases in children is low but is difficult to estimate because the majority of infections in children are asymptomatic. The risk of chronic infection is related inversely to age; although less than 10% of infections occur in children, these infections account for 20–30% of all chronic cases.

The most important risk factor for acquisition of hepatitis B infection in children is perinatal exposure to an HBsAg-positive mother. The risk of transmission is greatest if the mother also is HBeAg positive; 70–90% of their infants become chronically infected if untreated. During the neonatal period, hepatitis B antigen is present in the blood of 2.5% of infants born to affected mothers, indicating that intrauterine infection occurred. In most cases, antigenemia appears later, suggesting that transmission occurred at the time of delivery; virus contained in amniotic fluid or in maternal feces or blood may be the source. Although most infants born to infected mothers become antigenemic from 2–5 mo of age, some infants of HBsAg-positive mothers are not affected until later ages.

HBsAg has been demonstrated inconsistently in milk of infected mothers. Breast-feeding of unimmunized infants by infected mothers does not appear to confer a greater risk of hepatitis on offspring than does artificial feeding despite the possibility that cracked nipples may result in the ingestion of contaminated maternal blood by the nursing infant.

Other important risk factors for HBV infection in children include intravenous acquisition by drugs or blood products, sexual contact, institutional care, and contact with carriers. Chronic HBV infection, which is defined as being HBsAg positive for 6 or more mo, is associated with chronic liver disease and with primary hepatocellular carcinoma, the most important cause of cancer-related death in the Orient.

HBV is present in high concentrations in blood, serum, and serous exudates and in moderate concentrations in saliva, vaginal fluid, and semen. For these reasons, efficient transmission occurs through blood exposure and sexual contact. The incubation period ranges from 45–160 days, with a mean of about 100 days.

PATHOLOGY.

The acute response of the liver to HBV is the same as that for all the hepatitis viruses. Persistence of histologic changes in patients with hepatitis B, C, or D indicates development of chronic liver disease.

PATHOGENESIS.

Hepatitis B, unlike the other hepatitis viruses, is a noncytopathic virus that probably causes injury by immune-mediated mechanisms. The first step in the process of acute hepatitis is infection of hepatocytes by HBV, resulting in the appearance of viral antigens on the cell surface. The most important of these viral antigens may be the nucleocapsid antigens, HBcAg and HBeAg, a cleavage product of HBcAg. These antigens, in combination with class I major histocompatibility (MHC) proteins, make the cell a target for cytotoxic T-cell lysis.

The mechanism for development of chronic hepatitis is less well understood. To permit hepatocytes to continue to be infected, the core protein or MHC class I protein may not be recognized, the cytotoxic lymphocytes may not be activated, or some other as yet unknown mechanism may interfere with destruction of hepatocytes. For cell-to-cell infection to continue, some virus-containing hepatocytes must survive.

Immune-mediated mechanisms also are involved in the extrahepatic conditions that can be associated with HBV infections. Circulating immune complexes containing HBsAg can occur in patients who experience associated polyarteritis, glomerulonephritis, polymyalgia rheumatica, mixed cryoglobulinemia, and the Guillain-Barré syndrome.

Mutations of HBV are more common than for the usual DNA viruses, and a series of mutant strains have been recognized. The most important is one that results in failure to express HBeAg and has been associated with development of severe hepatitis and perhaps more severe exacerbations of chronic HBV infection.

CLINICAL MANIFESTATIONS.

Many cases of HBV infection are asymptomatic, as evidenced by the high carriage rate of serum markers in persons who have no history of acute hepatitis. The usual acute, symptomatic episode is similar to HAV and hepatitis C virus (HCV) infections but may be more severe and is more likely to include involvement of skin and joints. The first clinical evidence of HBV infection is elevation of ALT, which begins to rise just before the development of lethargy, anorexia, and malaise, about 6–7 wk after exposure. The illness may be preceded in a few children by a serum sickness–like prodrome including arthralgia or skin lesions, including urticarial, purpuric, macular, or maculopapular rashes. Papular acrodermatitis, the Gianotti-Crosti syndrome, also may occur. Other extrahepatic conditions associated with HBV infections include polyarteritis, glomerulonephritis, and aplastic anemia. Jaundice, which is present in about 25% of infected individuals, usually begins about 8 wk after exposure and lasts for about 4 wk. In the usual course of resolving HBV infection, symptoms are present for 6–8 wk. The percentage of people in whom clinical evidence of hepatitis develops is higher for hepatitis B than for hepatitis A, and the rate of fulminant hepatitis also is greater. Chronic hepatitis also occurs, and the chronic active form can result in cirrhosis and hepatocellular carcinoma.

On physical examination, skin and mucous membranes are icteric, especially the sclera and the mucosa under the tongue. The liver usually is enlarged and tender to palpation. When the liver is not palpable below the costal margin, tenderness can be demonstrated by striking the rib cage over the liver gently with a closed fist. Splenomegaly and lymphadenopathy are common.

DIAGNOSIS.

 The serologic pattern for HBV is more complex than for HAV and differs depending on whether the disease is acute, subclinical, or chronic.

Routine screening for hepatitis B requires assay of at least two serologic markers. HBsAg is the first serologic marker of infection to appear and is found in almost all infected persons; its rise coincides closely with the onset of symptoms. HBeAg is often present during the acute phase and indicates a highly infectious state. Because HBsAg levels fall before the end of symptoms, IgM antibody to hepatitis B core antigen (IgM anti-HBcAg) also is required because it rises early after infection and persists for many months before being replaced by IgG anti-HBcAg, which persists for years. IgM anti-HBcAg usually is not present in perinatal HBV infections. Anti-HBcAg is the most valuable single serologic marker of acute HBV infection because it is present almost as early as HBsAg and continues to be present later in the course of the disease when HBsAg has disappeared. Only anti-HBsAg is present in persons immunized with hepatitis B vaccine, whereas anti-HBsAg and anti-HBcAg are detected in persons with resolved infection.

COMPLICATIONS.

Acute fulminant hepatitis occurs more frequently with HBV than with the other hepatitis viruses, and the risk of fulminant hepatitis is further increased when there is coinfection or superinfection with HDV. Mortality from fulminant hepatitis is greater than 30%. Liver transplantation is the only effective intervention; supportive care aimed at sustaining the patient while providing the time needed for regeneration of hepatic cells is the only other option.

HBV infections also can result in chronic hepatitis, which can lead to cirrhosis and primary hepatocellular carcinoma. Interferon alpha-2b is available for treatment of chronic hepatitis B in persons 18 years of age or older with compensated liver disease and HBV replication. Membranous glomerulonephritis with deposition of complement and HBeAg in glomerular capillaries is a rare complication of HBV infection.

PREVENTION.

Universal immunization of infants with hepatitis B vaccine is now recommended by the American Academy of Pediatrics (AAP) and the U.S. Public Health Service because selective strategies failed to prevent the substantial morbidity and mortality associated with HBV infection. The neonatal period has been targeted because more than 90% of infants who acquire the infection perinatally will become chronic carriers. The risk of acquiring the chronic carrier state diminishes with age; 50% of older children and 10% of adults who become infected will become chronic carriers. Two recombinant DNA vaccines are available in the United States; both have proven to be highly immunogenic in children. The original plasma-derived vaccine is equally immunogenic but is no longer manufactured in the United States.

Infants born to HBsAg-positive women should receive vaccine at birth, 1 mo, and 6 mo of age. The first dose should be accompanied by administration of 0.5 mL of hepatitis B immunoglobulin (HBIG) as soon after delivery as possible because the effectiveness decreases rapidly with increased time after birth. The AAP recommends that infants born to HBsAg-negative women receive the first dose of vaccine at birth, the second at 1–2 mo of age, and the third between 6 and 18 mo of age.

The methods of prevention of hepatitis B infection depend on the conditions under which the person is exposed to hepatitis B, and the dose is dependent on the age of the person.


HEPATITIS C

ETIOLOGY. HCV is now recognized as the cause of almost all of the parenterally acquired cases of what was previously known as non-A, non-B hepatitis. The virus has not been isolated but has been cloned using recombinant DNA technology. Molecular biologic analysis has demonstrated that HCV is a single-strand RNA virus that has been classified as a separate genus within the Flaviviridae family. HCV is an enveloped virus, 50–60 nm in size, that is transmitted mainly by blood or blood products, intravenous drug use, and sexual contact. Chronic liver disease is common in infected individuals.

EPIDEMIOLOGY.
The most important risk factors for HCV transmission in the United States are the use of intravenous drugs (40%), transfusions (10%), and occupational and sexual exposure (10%). The remaining 40% of patients have no known associated risk factors. Perinatal transmission has been described but is uncommon except when the mother is HIV infected or has a high titer of HCV RNA. Although HCV testing has made blood transfusions much safer, testing of blood may result in only a modest decline in HCV cases because transfusions account for only a small percentage of HCV infections. Large population serosurveys in the United States indicate that approximately 1% of the adult population has evidence for previous HCV infection. The incubation period is 7–9 wk (range, 2–24 wk).

PATHOLOGY. The pattern of acute injury is similar to that of the other hepatitis viruses. In chronic cases, lymphoid aggregates or follicles in portal tracts are seen either alone or as part of a general inflammatory infiltration of the tracts.

PATHOGENESIS. HCV appears to cause injury primarily by cytopathic mechanisms, but immune-mediated injury also may occur. The cytopathic component appears to be mild, because the acute form is typically the least severe of all hepatitis virus infections; HCV rarely is fulminant.

CLINICAL MANIFESTATIONS.
The clinical pattern of the acute infection is usually similar to that of the other hepatitis viruses. HCV is the most likely hepatitis virus to cause chronic infection; about two thirds of post-transfusion infections and about one third of sporadic, community-acquired cases will become chronic. Typically, a fluctuating pattern of aminotransferase elevations occurs in about 80% of those in whom chronic HCV develops. Although chronic elevations of aminotransferase levels are common, chronic HCV will progress to cirrhosis in only about half of the patients, or about 25% of all those initially infected. Primary hepatocellular carcinoma can develop in patients with cirrhosis, but HCV is less effective than HBV in causing primary hepatocellular carcinoma. The hepatocellular carcinoma associated with HCV probably results from chronic inflammation and necrosis rather than an oncogenic effect of the virus.
Hepatitis C in the newborn

DIAGNOSIS.
The clinically available serologic assays for HCV are based on development of antibodies to HCV antigens because no detectable antigens have been found in blood. The assays are used mainly for detection of chronic hepatitis C because they remain negative for at least 1–3 mo after the clinical onset of illness. The second-generation assays are the current standard and test for three of the five known antigenic epitopes. They have improved sensitivity over the first-generation tests but still have a 10% false-negative rate. Assays for viral RNA (polymerase chain reaction [PCR], in situ hybridization) are costly, time consuming, and available only in research situations.

COMPLICATIONS.
The risk of fulminant hepatitis is low with HCV, but the risk for chronic hepatitis is the highest among the hepatitis viruses. The usual chronic course is mild even when cirrhosis develops; long-term follow-up indicates that the overall mortality of persons with transfusion-acquired HCV is no different from that of noninfected controls. Interferon alpha-2b is available for treatment of chronic hepatitis in persons 18 yr of age or older with compensated liver disease who have a history of blood or blood product exposure or who are HCV antibody positive or both.

PREVENTION.
There is no vaccine available, and none may be developed because animal studies suggest that HCV infection does not lead to protective immunity; the same individual can be infected multiple times with the same virus. Ig has not proven to be of benefit. Ig manufactured in the United States does not contain antibodies to HCV because blood and plasma donors are screened for anti-HCV, and exclusion of the HCV positive persons from the donor pool is recommended.


HEPATITIS D

 ETIOLOGY.
Hepatitis D virus (HDV), the smallest known animal virus, is considered defective because it cannot produce infection without a concurrent HBV infection. The 36-nm diameter virus is incapable of making its own coat protein; its outer coat is composed of excess HBsAg from HBV. The inner core of the virus is single-stranded circular RNA, which expresses the HDV antigen.

EPIDEMIOLOGY. HDV infection cannot occur without HBV as a helper virus. Two patterns of infection are seen. Transmission usually occurs by intrafamilial or intimate contact in areas of high prevalence, which are primarily developing countries. In areas of low prevalence, such as the United States, the percutaneous route is far more common. Hepatitis D infections are uncommon in children in the United States but must be considered when fulminant hepatitis occurs. In the United States, HDV infection is found most frequently in parenteral drug abusers, hemophiliacs, and persons immigrating from southern Italy, parts of eastern Europe, South America, Africa, and the Middle East. The incubation period for HDV superinfection is about 2–8 wk; with coinfection, the incubation period is similar to that of HBV infection.

PATHOLOGY. There are no distinguishing features of liver disease in HDV hepatitis except that the damage is usually more severe.

PATHOPHYSIOLOGY.
In contrast to HBV, HDV causes injury directly by cytopathic mechanisms. Many of the most severe cases of hepatitis B appear to be due to combined infection with HBV and HDV. Coinfection with HBV and HDV occurs most frequently in areas of high prevalence. The second mechanism of pathogenesis is superinfection of a person who has chronic HBV, which is more common in developed countries.

CLINICAL MANIFESTATIONS.
The symptoms of hepatitis D infection are similar to but usually more severe than those of the other hepatitis viruses. The clinical outcome for HDV infection depends on the mechanism of infection. In coinfection, acute hepatitis, which is much more severe than for HBV alone, is common, but the risk for chronic hepatitis is low. In superinfections, acute illness is rare, whereas chronic hepatitis is common. However, the risk of fulminant hepatitis is highest in superinfection. Hepatitis D should be considered in any child who experiences acute hepatic failure.

DIAGNOSIS.
The virus has not been isolated, and no circulating antigen has been identified. The diagnosis is made by detecting IgM antibody to HDV; the antibodies to HDV develop about 2–4 wk after coinfection and about 10 wk after superinfection. PCR assays for viral RNA are available but only as a research tool.

COMPLICATIONS. HDV must be considered in all cases of fulminant hepatitis.

PREVENTION. There is no vaccine for hepatitis D. However, because HDV cannot occur without hepatitis B infection, HBV prevention eliminates HDV. HBIG and hepatitis B vaccines are used for the same indications as hepatitis B.

HEPATITIS E

 ETIOLOGY. Hepatitis E virus (HEV) has not been isolated but has been cloned using molecular techniques. This RNA virus has a nonenveloped, sphere shape with spikes and is similar to the caliciviruses. Infection is associated with shedding of 27- to 34-nm particles in the stool.


EPIDEMIOLOGY. Hepatitis E is the epidemic form of what was formally called non-A, non-B hepatitis. Infection is transmitted enterically, the highest prevalence has been reported in the Indian subcontinent, the Middle East, and Southeast Asia, especially in areas with poor sanitation. In the United States, the only reported cases have been in persons who have visited or emigrated from endemic areas. The mean incubation period is about 40 days (range, 15–60 days).

PATHOLOGY. The pathologic findings are similar to those of the other hepatitis viruses.

PATHOGENESIS. HEV appears to act as a cytopathic virus.

CLINICAL MANIFESTATIONS. The clinical illness in hepatitis E is similar to that of hepatitis A, the other enterically transmitted virus, but it is often more severe. Both viruses produce only acute disease; chronic illness does not occur. In addition to causing more severe illness than HAV, hepatitis E affects older patients, with a peak incidence between 15 and 34 yr. Another important clinical difference is that HEV has a high fatality rate in pregnant women.

DIAGNOSIS.
Recombinant DNA technology has resulted in the development of an antibody to HEV particles, but serologic tests are not yet commercially available. IgM antibody to viral antigen becomes positive after about 1 wk of illness.

PREVENTION.
No vaccines are available, and there is no evidence that Ig is effective in preventing hepatitis E infections. However, Ig pooled from patients in endemic areas may prove to be effective.


Key words and phrases: Viral hepatitis, hepatitis A virus, hepatitis B virus, viral antigens, alanine aminotranspherase, aspartate aminotranspherase, Carole’s triad, “flu like syndrome”,  clay-colored stools, special hepatitis markers, prodromal period, jaundice period, conjugate bilirubin, bile pigments.

References:
Main:      
1.      Ambulatory pediatric care/ edited by Robert A. Derchewitz; - 2nd ed. – Lippincot – Raven, 1992. – p. 404-411, P.425-429.
2.      Current therapy in pediatric infections disease – 2/ edited by John D. Nelson, M.D. – B.C. Decker Inc. Toronto, Philadelphia, 1988. – p.74-77, 80-81.
3.      Principles and Practice of Pediatric Infectious Diseases. / Edited by Saran S. Long, Larry K. Pickering, Charles G. Prober, PhiladelphiaPa: Churchill Livingstone; 1997. – 1921 p.

Additional:
1.                         Cleary TG: Yersinia. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia: WB Saunders; 2000: 857-859.
2.                         Pickering L, ed: Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In: Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove VillageIllAmerican Academy of Pediatrics; 2000: 642-643.
3.                         Textbook of Pediatric Nursing.  Dorothy R. Marlow; R. N., Ed. D. –London, 1989.-661p.
4.                         Pediatrics ( 2nd edition, editor – Paul H.Dworkin, M.D.) – 1992. – 550 pp.
5.                         Behrman R.E., Kliegman R.M., Jenson H.B. Nelson nextbook of Pediatrics. - Saunders. - 2004. - 2618 p.
6.                         Castaneda C. Effects of Saccharomyces boulardii in children with Chronic Diarrhoea, Especially Due to Giardiasis // Revista Mexicana de Puericultura y Pediatria. - 1995. - V. 12. - P. 1462-1464.
7.                         Guidelines for control of shigellosis, icluding epidemics due to Shigella type 1/-World Health Organisation, 2005.
8.                         Implementing the New Recommendation on the Clinical Management of Diarrhoea. - World Health Organisation, 2006.
9.                         Klein J.D., Zaoutis T.E. Pediatric Infectious Disease Secrets. - Philedelphia: Hanley & Belfus Inc, 2003. - P. 142.

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