Differential Diagnosis

Often what brings the patient with hepatitis to medical attention is clinical icterus, which is a mixed or conjugated (direct) reacting hyperbilirubinemia.

Symptomatic infection results in icteric skin and mucous membranes. The liver is usually enlarged and tender to palpation and percussion. Splenomegaly and lymphadenopathy can be present. Extrahepatic symptoms are more readily seen in HBV and HCV infections (rashes, arthritis). Clinical signs of altered sensorium and hyperreflexivity should be carefully sought, because they mark the onset of encephalopathy and ALF.

The differential diagnosis varies with age of presentation.

In the newborn period, infection is a common cause of conjugated hyperbilirubinemia; the infectious cause is either a bacterial agent (Escherichia coli, Listeria, Syphilis) or one of the nonhepatotropic viruses (HSV, enteroviruses, CMV). Metabolic and anatomic causes (tyrosinemia, biliary atresia, genetic forms of intrahepatic cholestasis, and choledochal cysts) should always be excluded.

In later childhood, extrahepatic obstruction (gallstones, primary sclerosing cholangitis, pancreatic pathology), inflammatory conditions (autoimmune hepatitis, juvenile rheumatoid arthritis, Kawasaki disease, immune dysregulation), infiltrative disorders (malignancies), toxins and medications, metabolic disorders (Wilson disease, cystic fibrosis), and infection (EBV, varicella, malaria, leptospirosis, syphilis) should be ruled out.

Pathogenesis

The acute response of the liver to hepatotropic viruses involves a direct cytopathic and an immune-mediated injury. The entire liver is involved. Necrosis is usually most marked in the centrilobular areas. An acute mixed inflammatory infiltrate predominates in the portal areas but also affects the lobules. The lobular architecture remains intact, although balloon degeneration and necrosis of single or groups of parenchymal cells occurs commonly. Fatty change is rare except with HCV infection. Bile duct proliferation but not bile duct damage is common. Diffuse Kupffer cell hyperplasia is noticeable in the sinusoids. Neonates often respond to hepatic injury by forming giant cells.

In fulminant hepatitis, parenchymal collapse occurs on the just-described background.

With recovery, the liver morphology returns to normal within 3 mo of the acute infection. If chronic hepatitis develops, the inflammatory infiltrate settles in the periportal areas and often leads to progressive scarring. Both of these hallmarks of chronic hepatitis are seen in cases of HBV and HCV.

Common Biochemical Profiles in the Acute Infectious Phase

Acute liver injury caused by the hepatotropic viruses manifests in 3 main functional liver biochemical profiles. These serve as an important guide to supportive care and monitoring in the acute phase of the infection for all viruses.

As a reflection of cytopathic injury to the hepatocytes, there is a rise in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The magnitude of enzyme elevation does not correlate with the extent of hepatocellular necrosis and has little prognostic value. There is usually slow improvement over several weeks, but AST and ALT levels lag behind the serum bilirubin level, which tends to normalize first. Rapidly falling aminotransferase levels can predict a poor outcome, particularly if their decline occurs in conjunction with a rising bilirubin level and a prolonged prothrombin time; this combination of findings usually indicates that massive hepatic injury has occurred.

Cholestasis, defined by elevated serum conjugated bilirubin levels, results from abnormal bile flow at the canalicular and cellular level due to hepatocyte damage and inflammatory mediators. Elevation of serum alkaline phosphatase (ALP), 5′-nucleotidase, γ-glutamyl transpeptidase (GGT), and urobilinogen all mark cholestasis. Improvement tends to parallel the acute hepatitis phase. Absence of cholestatic markers does not rule out progression to chronicity in HCV or HBV infections.

The most important marker of liver injury is altered synthetic function. Monitoring of synthetic function should be the main focus in clinical follow-up to define the severity of the disease. In the acute phase, the degree of liver synthetic dysfunction guides treatment and helps to establish intervention criteria. Abnormal liver synthetic function is a marker of liver failure and is an indication for prompt referral to a transplant center. Serial assessment is necessary because liver dysfunction does not progress linearly. Synthetic dysfunction is reflected by a combination of abnormal protein synthesis (prolonged prothrombin time, high international normalized ratio [INR], low serum albumin levels), metabolic disturbances (hypoglycemia, lactic acidosis, hyperammonemia), poor clearance of medications dependent on liver function, and altered sensorium with increased deep tendon reflexes (hepatic encephalopathy; Chapter 356).

Etiology

HAV is an RNA virus, a member of the picornavirus family. It is heat stable and has limited host range—namely, the human and other primates.

Epidemiology

HAV infection occurs throughout the world but is most prevalent in developing countries. In the United States, 30-40% of the adult population has evidence of previous HAV infection. Hepatitis A is thought to account for ∼50% of all clinically apparent acute viral hepatitis in the United States. As a result of aggressive implementation of a childhood vaccination strategy, the prevalence of symptomatic HAV cases in the United States has declined significantly. However, outbreaks in daycare centers (where the spread from young, nonicteric, infected children can occur easily) as well as multiple foodborne and waterborne outbreaks have justified the implementation of a universal vaccination program.

HAV is highly contagious. Transmission is almost always by person-to-person contact through the fecal-oral route. Perinatal transmission occurs rarely. No other form of transmission is recognized. HAV infection during pregnancy or at the time of delivery does not appear to result in increased complications of pregnancy or clinical disease in the newborn. In the USA, increased risk of infection is found in contacts with infected persons, child-care centers, and household contacts. Infection has also been associated with contact with contaminated food or water and after travel to endemic areas. Common source foodborne and waterborne outbreaks have occurred, including several due to contaminated shellfish, frozen berries, and raw vegetables; no known source is found in about half of the cases. The mean incubation period for HAV is ∼3 wk. Fecal excretion of the virus starts late in the incubation period, reaches its peak just before the onset of symptoms, and resolves by 2 wk after the onset of jaundice in older subjects. The duration of viral excretion is prolonged in infants. The patient is therefore contagious before clinical symptoms are apparent and remains so until viral shedding ceases.

Clinical Manifestations

HAV is responsible for acute hepatitis only. Often, this is an anicteric illness, with clinical symptoms indistinguishable from other forms of viral gastroenteritis, particularly in young children.

The illness is much more likely to be symptomatic in older adolescents or adults, in patients with underlying liver disorders, and in those who are immunocompromised. It is characteristically an acute febrile illness with an abrupt onset of anorexia, nausea, malaise, vomiting, and jaundice. The typical duration of illness is 7-14 days (Fig. 350-1).

Figure 350-1 The serologic course of acute hepatitis A. ALT, alanine aminotransferase; HAV, hepatitis A virus.

(From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p 913.)

Other organ systems can be affected during acute HAV infection. Regional lymph nodes and the spleen may be enlarged. The bone marrow may be moderately hypoplastic, and aplastic anemia has been reported. Tissue in the small intestine might show changes in villous structure, and ulceration of the gastrointestinal tract can occur, especially in fatal cases. Acute pancreatitis and myocarditis have been reported, though rarely, and nephritis, arthritis, vasculitis, and cryoglobulinemia can result from circulating immune complexes.

Diagnosis

Acute HAV infection is diagnosed by detecting antibodies to HAV, specifically, anti-HAV (IgM) by radioimmunoassay or, rarely, by identifying viral particles in stool. A viral polymerase chain reaction (PCR) assay is available for research use (Table 350-3). Anti-HAV is detectable when the symptoms are clinically apparent, and it remains positive for 4-6 mo after the acute infection. A neutralizing anti-HAV (IgG) is usually detected within 8 wk of symptom onset and is measured as part of a total anti-HAV in the serum. Anti-HAV (IgG) confers long-term protection.

Rises in serum levels of ALT, AST, bilirubin, ALP, 5′-nucleotidase, and GGT are almost universally found and do not help to differentiate the cause of hepatitis.

Complications

Although most patients achieve full recovery, two distinct complications can occur.

ALF from HAV infection is a rare but not infrequent complication of HAV. Those at risk for this complication are adolescents and adults, but also patients with underlying liver disorders or those who are immunocompromised. The height of HAV viremia may be linked to the severity of hepatitis. Whereas in the United States, HAV represents <0.5% of pediatric-aged ALF, it is responsible for up to 3% mortality in the adult population with ALF. In endemic areas of the world, HAV constitutes up to 40% of all cases of pediatric ALF.

HAV can progress to a prolonged cholestatic syndrome that waxes and wanes over several months. Pruritus and fat malabsorption are problematic and require symptomatic support with antipruritic medications and fat-soluble vitamins. This syndrome occurs in the absence of any liver synthetic dysfunction and resolves with no sequelae.

Treatment

There is no specific treatment for hepatitis A. Supportive treatment consists of intravenous hydration as needed and antipruritic agents and fat-soluble vitamins for the prolonged cholestatic form of disease. Serial monitoring for signs of ALF and, if ALF is diagnosed, a prompt referral to a transplantation center can be lifesaving.

Prevention

Patients infected with HAV are contagious for 2 wk before and ~7 days after the onset of jaundice and should be excluded from school, child care, or work during this period. Careful handwashing is necessary, particularly after changing diapers and before preparing or serving food. In hospital settings, contact and standard precautions are recommended for 1 wk after onset of symptoms.

Prognosis

The prognosis for the patient with hepatitis A is excellent, with no long-term sequelae. The only feared complication is ALF. HAV infection remains a cause of major morbidity, however, and has a high socioeconomic impact during epidemics and in endemic areas.

Etiology

HBV is a member of the Hepadnaviridae family. HBV has a circular, partially double-stranded DNA genome composed of ∼3,200 nucleotides. Four genes have been identified: the S (surface), C (core), X, and P (polymer) genes. The surface of the virus includes particles designated hepatitis B surface antigen (HBsAg), which is 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), the nucleocapsid that encodes the viral DNA, and a nonstructural antigen called hepatitis B e antigen (HBeAg), a nonparticulate soluble antigen derived from HBcAg by proteolytic self-cleavage. HBeAg serves as a marker of active viral replication and usually correlates with HBV DNA levels. Replication of HBV occurs predominantly in the liver but also occurs in the lymphocytes, spleen, kidney, and pancreas.

Epidemiology

HBV has been detected worldwide, with an estimated 400 million persons chronically infected. The areas of highest prevalence of HBV infection are sub-Saharan Africa, China, parts of the Middle East, the Amazon basin, and the Pacific Islands. In the United States, the native population in Alaska had the highest prevalence rate before the implementation of universal vaccination programs. An estimated 1.25 million persons in the United States are chronic HBV carriers, with ∼300,000 new cases of HBV occurring each year, the highest incidence being among adults 20-39 yr of age. One in 4 chronic HBV carriers will develop serious sequelae in their lifetime. The number of new cases in children reported each year is thought to be low but is difficult to estimate because many infections in children are asymptomatic. In the United States, since 1982 when the first vaccine for HBV was introduced, the overall incidence of HBV infection has been reduced by more than half. Since the implementation of universal vaccination programs in Taiwan and the United States, substantial progress has been made toward eliminating HBV infection in children in these countries.

HBV is present in high concentrations in blood, serum, and serous exudates and in moderate concentrations in saliva, vaginal fluid, and semen. Efficient transmission occurs through blood exposure and sexual contact. Risk factors for HBV infection in children and adolescents include acquisition by intravenous drugs or blood products and by acupuncture or tattoos, sexual contact, institutional care, and intimate contact with carriers. No risk factors are identified in ∼40% of cases. HBV is not thought to be transmitted via indirect exposure such as sharing toys.

In children, the most important risk factor for acquisition of HBV remains perinatal exposure to an HBsAg-positive mother. The risk of transmission is greatest if the mother is also HBeAg positive; up to 90% of these infants become chronically infected if untreated. Intrauterine infection occurs in 2.5% of these infants. In most cases, serologic markers of infection and antigenemia appear 1-3 mo after birth, suggesting that transmission occurred at the time of delivery. Virus contained in amniotic fluid or in maternal feces or blood may be the source. Immunoprophylaxis of those infants is very effective in preventing infection and protects >95% of neonates. Of the 22,000 infants born each year to HBsAg-positive mothers in the United States, >98% receive immunoprophylaxis and are thus protected.

HBsAg is inconsistently recovered in human milk of infected mothers. Breast-feeding of nonimmunized infants by infected mothers does not confer a greater risk of hepatitis than does formula feeding.

The risk of developing chronic HBV infection, defined as being positive for HBsAg for >6 mo, is inversely related to age of acquisition. In the United States, although <10% of infections occurs in children, these infections account for 20-30% of all chronic cases. This risk of chronic infection is 90% in children <1 yr; the risk is 30% for those 1-5 yr and 2% for adults. Chronic infection is associated with the development of chronic liver disease and hepatocellular carcinoma. The carcinoma risk is independent of the presence of cirrhosis and was the most prevalent cancer-related death in young adults in Asia where HBV was endemic.

HBV has 8 genotypes (A-H). A is pandemic, B and C are prevalent in Asia, D is seen in Southern Europe, E in Africa, F in the United States, G in the United States and France, and H in Central America. Genetic variants have become resistant to antiviral agents. After infection, the incubation period ranges from 45 to 160 days, with a mean of ~120 days.

Pathogenesis

The acute response of the liver to HBV is the same as for all hepatotropic viruses. Persistence of histologic changes in patients with hepatitis B indicates development of chronic liver disease. HBV, unlike the other hepatotropic viruses, is a predominantly non-cytopathogenic virus that causes injury mostly by immune-mediated processes. The severity of hepatocyte injury reflects the degree of the immune response, with the most complete immune response being associated with the greatest likelihood of viral clearance but also the most severe injury to hepatocytes. The first step in the process of acute hepatitis is infection of hepatocytes by HBV, resulting in expression of viral antigens on the cell surface. The most important of these viral antigens may be the nucleocapsid antigens HBcAg and HBeAg. 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 might not be recognized, the cytotoxic lymphocytes might not be activated, or some other, yet unknown mechanism might interfere with destruction of hepatocytes. This tolerance phenomenon predominates in the cases acquired perinatally, resulting in a high incidence of persistent infection in children with no or little inflammation in the liver. Although end-stage liver disease rarely develops in those patients, the inherent hepatocellular carcinoma risk is very high, possibly related, in part, to uncontrolled viral replication cycles.

ALF has been seen in infants of chronic carrier mothers who have anti-HBe or are infected with a precore-mutant strain. This fact led to the postulate that HBeAg exposure in utero in infants of chronic carriers likely induces tolerance to the virus once infection occurs postnatally. In the absence of this tolerance, the liver is massively attacked by T cells and the patient presents with ALF.

Immune-mediated mechanisms are also involved in the extrahepatic conditions that can be associated with HBV infections. Circulating immune complexes containing HBsAg can occur in patients who develop associated polyarteritis nodosa, membranous or membranoproliferative glomerulonephritis, polymyalgia rheumatica, leukocytoclastic vasculitis, and Guillain-Barré syndrome.

Clinical Manifestations

Many acute cases of HBV infection in children 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 that of HAV and HCV infections but may be more severe and is more likely to include involvement of skin and joints (Fig. 350-2). The first biochemical evidence of HBV infection is elevation of serum ALT levels, which begin to rise just before development of fatigue, anorexia, and malaise, which occurs about 6-7 wk after exposure. The illness is preceded in a few children by a serum sickness–like prodrome marked by arthralgia or skin lesions, including urticarial, purpuric, macular, or maculopapular rashes. Papular acrodermatitis, the Gianotti-Crosti syndrome, can also occur. Other extrahepatic conditions associated with HBV infections in children include polyarteritis, glomerulonephritis, and aplastic anemia. Jaundice, which is present in ∼25% of acutely infected patients, usually begins ∼8 wk after exposure and lasts for ∼4 wk.

Figure 350-2 The serologic course of acute hepatitis B. HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBs, hepatitis B surface; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction.

(From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p 914.)

In the usual course of resolving HBV infection, symptoms are present for 6-8 wk. The percentage of children in whom clinical evidence of hepatitis develops is higher for HBV than for HAV, and the rate of ALF is also greater. Most patients do recover, but the “chronic carrier state” complicates up to 10% of cases acquired in adulthood. The rate of acquisition of chronic infection depends largely on the mode and age of acquisition and is up to 90% in the perinatal cases. Chronic hepatitis, cirrhosis, and hepatocellular carcinoma are only seen with chronic infection. Chronic HBV infection has 3 identified phases: immune tolerant, immune active, and inactive. Most children fall in the immune-tolerant phase, against which no effective therapy is yet developed, but most treatments target the immune active phase of the disease, characterized by active inflammation, elevated ALT/AST levels, and progressive fibrosis. Spontaneous HBeAg seroconversion occurs in the immune-tolerant phase, albeit at low rates of 4-5% per year. It is more common in childhood-acquired HBV rather than in vertically transmitted infections. Seroconversion can last many years, during which significant damage to the liver can happen. There are no large studies that help accurately assess the lifelong risks and morbidities of children with chronic HBV infection, making the timing of still less-than-ideal treatments ever so hard to decide. Reactivation of chronic infection has been reported in immunosuppressed children (treated with chemotherapy, biologic immunomodulators, T-cell depleting agents), leading to an increased risk of ALF or to rapidly progressing fibrotic liver disease.

Diagnosis

The serologic profile of HBV infection is more complex than for HAV infection and differs depending on whether the disease is acute or chronic (Fig. 350-3). Several antigens and antibodies are used to confirm the diagnosis of acute HBV infection (see Table 350-3). Routine screening for HBV infection requires assay of ≥3 serologic markers (HBsAg, anti-HBc, anti-HBs). HBsAg is the first serologic marker of infection to appear and is found in almost all infected persons; its rise closely coincides with the onset of symptoms. Persistence of HBsAg beyond 6 mo defines the chronic infection state. During recovery from acute infection, because HBsAg levels fall before symptoms wane, IgM antibody to HBcAg (anti-HBc IgM) might be the only marker of acute infection. Anti-HBc IgM rises early after the infection and remains positive for many months before being replaced by anti-HBc IgG, which then persists for years. Anti-HBc is therefore a valuable serologic marker of acute HBV infection. Anti-HBs marks serologic recovery and protection. Only anti-HBs is present in persons immunized with hepatitis B vaccine, whereas both anti-HBs and anti-HBc are detected in persons with resolved infection. HBeAg is present in active acute or chronic infection and is a marker of infectivity. The development of anti-HBe marks improvement and is a goal of therapy in chronically infected patients. HBV DNA can be detected in the serum of acutely infected patients and chronic carriers. High DNA titers are seen in patients with HBeAg, and they typically fall once anti-HBe develops.

Figure 350-3 Natural history of hepatitis B virus infection. HCC, hepatocellular carcinoma; OLT, orthotopic liver transplant.

Complications

ALF with coagulopathy, encephalopathy, and cerebral edema occurs more commonly with HBV than with the other hepatotropic viruses. The risk of ALF is further increased when there is co-infection or super-infection with HDV and in an immunosuppressed host. Mortality due to ALF is >30%, and liver transplantation is the only effective intervention. Supportive care aimed at sustaining patients and early referral to a liver transplantation center can be lifesaving. As mentioned, HBV infection can also result in chronic hepatitis, which can lead to cirrhosis, end-stage liver disease complications, and primary hepatocellular carcinoma. Membranous glomerulonephritis with deposition of complement and HBeAg in glomerular capillaries is a rare complication of HBV infection.

Treatment

Treatment of acute HBV infection is largely supportive. Close monitoring for liver failure and extrahepatic morbidities is key.

Treatment of chronic HBV infection is in evolution; no one drug currently achieves reliably complete eradication of the virus. The natural history of HBV chronic infection in children is complex, and there is a lack of reliable long-term outcome data on which to base treatment recommendation. Treatment of chronic HBV infection in children should be individualized and done under the care of a pediatric gastroenterologist experienced in treating liver disease.

The goal of treatment is to reduce viral replication as defined by undetectable HBV DNA in the serum and development of anti-HBe. This seroconversion transforms the disease into an inactive form, therefore decreasing active liver injury and inflammation, fibrosis progression, and infectivity as well as the risk of hepatocellular carcinoma.

Currently, treatment is only indicated for patients in the immune-active form of the disease, with evidence of ongoing inflammation and fibrosis putting the child at higher risk for cirrhosis during childhood.

Prevention

Hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) are available for prevention of HBV infection. Two recombinant DNA vaccines are available in the United States; both are highly immunogenic in children. The safety profile of HBV vaccine is excellent. The most reported side effects are pain at the injection site (up to 29% of cases) and fever (up to 6% of cases).

Household, sexual, and needle-sharing contacts should be identified and vaccinated if they are susceptible to HBV infection. Patients should be advised about the perinatal and intimate contact risk of transmission of HBV. HBV is not spread by breast-feeding, kissing, hugging, or sharing water or utensils. Children with HBV should not be excluded from school, play, child care, or work, unless they are prone to biting. A support group might help children to cope better with their disease. All patients positive for HBsAg should be reported to the state or local health department, and chronicity is diagnosed if they remain positive past 6 mo.

Postexposure Prophylaxis

Recommendations for postexposure prophylaxis for prevention of hepatitis B infection depend on the conditions under which the person is exposed to HBV (see Table 350-5). Vaccination should never be postponed if written records of the exposed person’s immunization history are not available, but every effort should still be made to obtain those records.

Prognosis

In general, the outcome after acute HBV infection is favorable, despite a risk of ALF. The risk of developing chronic infection brings the risks of liver cirrhosis and hepatocellular carcinoma to the forefront. Perinatal transmission leading to chronicity is responsible for the high incidence of hepatocellular carcinoma in young adults in the endemic areas. Importantly, HBV infection and its complications are effectively controlled and prevented with vaccination.

Etiology

HCV is a single-stranded RNA virus, classified as a separate genus within the Flaviviridae family, with marked genetic heterogeneity. It has 6 major genotypes and numerous subtypes and quasi-species, which permit the virus to escape host immune surveillance. Genotype variation might partially explain the differences in clinical course and response to treatment. Genotype 1b is the most common genotype in the United States and is the least responsive to the currently available medications.

Epidemiology

In the United States, HCV infection is the most common cause of chronic liver disease in adults and causes 8,000-10,000 deaths per year. About 4 million people in the United States and 170 million people worldwide are estimated to be infected with HCV. Approximately 85% of infected adults remain chronically infected. In children, seroprevalence of HCV is 0.2% in children <11 yr of age and 0.4% in children ≥11 yr of age.

Risk factors for HCV transmission in the United States previously included blood transfusion as the most common route of infection, but, with the current screening practices, the risk of HCV transmission is now about 0.001% per unit transfused. Illegal drug use with exposure to blood or blood products from HCV-infected persons accounts for more than half of adult cases in the United States. Sexual transmission, especially through multiple sexual partners, is the second most common cause of infection. Other risk factors include occupational exposure; ∼10% of new infections has no known transmission source. In children, perinatal transmission is the most prevalent mode of transmission (see Table 350-1). Perinatal transmission occurs in up to 5% of infants born to viremic mothers. HIV co-infection and high viremia titers (HCV RNA positive) in the mother can increase the transmission rate to 20%. The incubation period is 7-9 wk (range, 2-24 wk).

Pathogenesis

The pattern of acute hepatic injury is indistinguishable from that of other hepatotropic viruses. In chronic cases, lymphoid aggregates or follicles in portal tracts are found, either alone or as part of a general inflammatory infiltration of the tracts. Steatosis is also often seen in these liver specimens. HCV appears to cause injury primarily by cytopathic mechanisms, but immune-mediated injury can also occur. The cytopathic component appears to be mild, because the acute illness is typically the least severe of all hepatotropic virus infections.

Clinical Manifestations

Acute HCV infection tends to be mild and insidious in onset (Fig. 350-4; see also Table 350-1). ALF rarely occurs. HCV is the most likely hepatotropic virus to cause chronic infection (Fig. 350-5). Of affected adults, <15% clear the virus; the rest develop chronic hepatitis. In pediatric studies, 6-19% of children achieved spontaneous sustained clearance of the virus during a 6 yr follow-up.

Figure 350-4 The serologic course of acute hepatitis C. ALT, alanine aminotransferase; HCV, hepatitis C virus; PCR, polymerase chain reaction.

(From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p 915.)

Figure 350-5 Natural history of hepatitis C virus infection. HCC, hepatocellular carcinoma; OLT, orthotopic liver transplant.

(From Hochman JA, Balistreri WF: Chronic viral hepatitis: always be current! Pediatr Rev 24:399–410, 2003.)

Chronic HCV infection is also clinically silent until a complication develops. Serum aminotransferase levels fluctuate and are sometimes normal, but histologic inflammation is universal. Progression of liver fibrosis is slow over several years, unless comorbid factors are present, which can accelerate fibrosis progression. About 25% of infected patients ultimately progress to cirrhosis, liver failure, and, occasionally, primary hepatocellular carcinoma (HCC) within 20-30 yr of the acute infection. Although progression is rare within the pediatric age range, cirrhosis and HCC from HCV have been reported in children. The long-term morbidities constitute the rationale for diagnosis and treatment in children with HCV.

Chronic HCV infection can be associated with small vessel vasculitis and is a common cause of essential mixed cryoglobulinemia. Other extrahepatic manifestations predominantly seen in adults include cutaneous vasculitis, peripheral neuropathy, cerebritis, membranoproliferative glomerulonephritis, and nephrotic syndrome. Antibodies to smooth muscle, antinuclear antibodies, and low thyroid hormone levels may also be present.

Diagnosis

Clinically available assays for detection of HCV infection are based on detection of antibodies to HCV antigens or detection of viral RNA (see Table 350-3); neither can predict the severity of liver disease.

The most widely used serologic test is the third-generation enzyme immunoassay (EIA) to detect anti-HCV. The predictive value of this assay is greatest in high-risk populations, but the false-positive rate can be as high as 50-60% in low-risk populations. False-negative results also occur because antibodies remain negative for as long as 1-3 mo after clinical onset of illness. Anti-HCV is not a protective antibody and does not confer immunity; it is usually present simultaneously with the virus.

The most commonly used virologic assay for HCV is a PCR assay, which permits detection of small amounts of HCV RNA in serum and tissue samples within days of infection. The qualitative PCR detection is especially useful in patients with recent or perinatal infection, hypogammaglobulinemia, or immunosuppression and is very sensitive. The quantitative PCR aids in identifying patients who are likely to respond to therapy and in monitoring response to therapy.

Screening for HCV should include all patients with the following risk factors: history of illegal drug use (even if only once), receiving clotting factors made before 1987 (when inactivation procedures were introduced) or blood products before 1992, hemodialysis, idiopathic liver disease, and children born to HCV-infected women (qualitative PCR in infancy and anti-HCV after 12 mo of age). Routine screening of all pregnant women is not recommended.

Determining HCV genotype is also important, particularly when therapy is considered, because the response to the current therapeutic agents varies greatly. Genotype 1 is poorly responsive; genotypes 2 and 3 are more reliably responsive to therapy (as discussed later).

Aminotransferase levels typically fluctuate during HCV infection and do not correlate with the degree of liver fibrosis.

A liver biopsy is the only means to assess the presence and extent of hepatic fibrosis, outside of overt signs of chronic liver disease. A liver biopsy is indicated only before starting any treatment and to rule out other causes of overt liver disease.

Complications

The risk of ALF due to HCV is low, but the risk of chronic hepatitis is the highest of all the hepatotropic viruses. In adults, risk factors for progression to hepatic fibrosis include older age, obesity, male sex, and even moderate alcohol ingestion (two 1 oz drinks per day). Progression to cirrhosis or HCC is a major cause of morbidity and the most common indication for liver transplantation in adults in the United States.

Treatment

In adults, peginterferon (subcutaneous, weekly) combined with oral daily ribavirin is the most effective therapy. Studies incorporate, in addition, nucleoside analogs. Patients most likely to respond have mild hepatitis, shorter duration of infection, and low viral titers. Genotypes 2 and 3 are the most sensitive to treatment; patients with genotype 1 virus respond poorly. The goal of treatment is to achieve a sustained viral response (SVR), as defined by the absence of viremia 6 mo after stopping the medications; SVR is associated with improved histology and decreased risk of morbidities.

The natural history of HCV infection in children is still being defined. It is believed that children have a higher rate of spontaneous clearance than in adults (up to 45% by age 19 yr). A multicenter study followed 359 children infected with HCV over 10 yr. Only 7.5% had cleared the virus, and 1.8% progressed to decompensated cirrhosis. Treatment in adults with acute HCV in a pilot study showed an 88% sustained viral response (SVR) in genotype 1 subjects (treated with IFN and ribavarin for 24 wk). Such data, if confirmed, could actually raise the question whether children, with shorter duration of infection and fewer comorbid conditions than their adult counterparts, could be “ideal” candidates for treatment. Given the adverse effects of currently available therapy, this strategy is not recommended outside of clinical trials.

Peginterferon (Schering), IFN-α2b, and ribavirin are approved by the Food and Drug Administration (FDA) for use in children >3 yr of age with HCV hepatitis. Studies of IFN monotherapy in children have shown a higher SVR than in adults, with better compliance and fewer side effects. An SVR up to 49% for genotype 1 was achieved in multiple studies. Factors associated with a higher likelihood of response are age <12 yr, genotypes 2 and 3, and, in patients with genotype 1b, an RNA titer <2 million copies/mL of blood, and viral response (PCR at weeks 4 and 12 of treatment). Side effects of medications lead to discontinuation of treatment in a high proportion of patients; these include anemia, neutropenia, and influenza-like symptoms.

Treatment should be considered for all children infected with genotypes 2 and 3, because they have a high response rate to therapy. If the child has genotype type 1b virus, the treatment choice remains more controversial. Treatment should be considered for patients with evidence of advanced fibrosis or injury on liver biopsy. A consensus recommendation paper suggested considering treatment in all patients with evidence of active inflammation on a liver biopsy along with biochemical anomalies. Treatment consists of 48 wk of IFN and ribavarin (therapy should be stopped if still detectable on viral PCR at 24 wk of therapy). A liver biopsy was recommended before treatment. Close monitoring for treatment side effects was encouraged. Treatment of children with normal biochemical profile and mild histologic inflammation should be reserved to a clinical study context.

Prevention

No vaccine is available to prevent HCV. Current immunoglobulin preparations are not beneficial, likely because immunoglobulin preparations produced in the United States do not contain antibodies to HCV because blood and plasma donors are screened for anti-HCV and excluded from the donor pool. Broad neutralizing antibodies to HCV were found to be protective and might pave the road for vaccine development.

Once HCV infection is identified, patients should be screened yearly with a liver ultrasound and serum α-fetoprotein for HCC, as well as for any clinical evidence of liver disease. Vaccinating the affected patient against HAV and HBV will prevent super-infection with these viruses and the increased risk of developing severe liver failure.

Prognosis

Viral titers should be checked yearly to document spontaneous remission. Most patients develop chronic hepatitis. Progressive liver damage is higher in those with additional comorbid factors such as alcohol consumption, viral genotypic variations, obesity, and underlying genetic predispositions. Referral to a pediatric gastroenterologist is strongly advised to take advantage of up-to-date monitoring regimens and to optimize their enrollment in treatment protocols when available.

Etiology

HDV, the smallest known animal virus, is considered defective because it cannot produce infection without 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 that expresses the HDV antigen.

Epidemiology

HDV can cause an infection at the same time as the initial HBV infection (co-infection), or HDV can infect a person who is already infected with HBV (super-infection). Transmission usually occurs by intrafamilial or intimate contact in areas of high prevalence, which are primarily developing countries (see Table 350-1). In areas of low prevalence, such as the United States, the parenteral route is far more common. HDV infections are uncommon in children in the United States but must be considered when ALF occurs. The incubation period for HDV super-infection is about 2-8 wk; with co-infection, the incubation period is similar to that of HBV infection.

Pathogenesis

Liver pathology in HDV hepatitis has no distinguishing features except that damage is usually quite severe. In contrast to HBV, HDV causes injury directly by cytopathic mechanisms. Many of the most severe cases of HBV infection appear to be a result of co-infection of HBV and HDV.

Clinical Manifestations

The symptoms of hepatitis D infection are similar to but usually more severe than those of the other hepatotropic viruses. The clinical outcome for HDV infection depends on the mechanism of infection. In co-infection, acute hepatitis, which is much more severe than for HBV alone, is common, but the risk of developing chronic hepatitis is low. In super-infection, acute illness is rare and chronic hepatitis is common. The risk of ALF is highest in super-infection. Hepatitis D should be considered in any child who experiences ALF.

Diagnosis

HDV 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 ∼2-4 wk after co-infection and ∼10 wk after a super-infection. A test for anti-HDV antibody is commercially available. PCR assays for viral RNA are available as research tools (see Table 350-2).

Complications

HDV must be considered in all cases of ALF. Co-infection with HBV can also result in a more severe chronic disease.

Treatment

The treatment is based on supportive measures once an infection is identified. There are no specific HDV-targeted treatments to date. The treatment is mostly based on controlling and treating HBV infection, without which HDV cannot induce hepatitis.

Prevention

There is no vaccine for hepatitis D. Because HDV replication cannot occur without hepatitis B co-infection, immunization against HBV also prevents HDV infection. Hepatitis B vaccines and HBIG are used for the same indications as for hepatitis B alone.

Etiology

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 in structure to the caliciviruses.

Epidemiology

Hepatitis E is the epidemic form of what was formerly called non-A, non-B hepatitis. Transmission is fecal-oral (often waterborne) and is associated with shedding of 27-34 nm particles in the stool (see Table 350-1). The highest prevalence of HEV infection has been reported in the Indian subcontinent, the Middle East, Southeast Asia, and Mexico, especially in areas with poor sanitation. The mean incubation period is ∼40 days (range, 15-60 days).

Pathogenesis

HEV appears to act as a cytopathic virus. The pathologic findings are similar to those of the other hepatitis viruses.

Clinical Manifestations

The clinical illness associated with HEV infection is similar to that of HAV but is often more severe. As with HAV, chronic illness does not occur. In addition to often causing a more severe episode than HAV, HEV tends to affect older patients, with a peak age between 15 and 34 yr. HEV is a major pathogen in pregnant women, in whom it causes ALF with a high fatality incidence. HEV could also lead to decompensation of pre-existing chronic liver disease.

Complications

HEV is associated with a high risk of death in pregnant women. No other complications are recognized in association with this virus.

Diagnosis

Recombinant DNA technology has resulted in development of antibodies to HEV particles, and IgM and IgG assays are available to distinguish between acute and resolved infections (see Table 350-3). IgM antibody to viral antigen becomes positive after ∼1 wk of illness. Viral RNA can be detected in stool and serum by PCR.

Prevention

A recombinant hepatitis E vaccine is highly effective in adults. No evidence suggests that immunoglobulin is effective in preventing HEV infections. Immunoglobulin pooled from patients in endemic areas might prove to be effective.