Viral Hepatitis

Differential Diagnosis

Often what brings the patient with hepatitis to medical attention is clinical icterus, with yellow skin and/or mucous membranes. The liver is usually enlarged and tender to palpation and percussion. Splenomegaly and lymphadenopathy may be present. Extrahepatic symptoms (rashes, arthritis) are more commonly seen in HBV and HCV infections. Clinical signs of bleeding, altered sensorium, or hyperreflexia 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 (e.g., Escherichia coli , Listeria, syphilis) or a nonhepatotropic virus (e.g., enteroviruses, cytomegalovirus, and herpes simplex virus, which may also cause a nonicteric severe hepatitis). Metabolic diseases (α ₁ -antitrypsin deficiency, cystic fibrosis, tyrosinemia), anatomic causes (biliary atresia, choledochal cysts), and inherited forms of intrahepatic cholestasis should always be excluded.

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

Pathogenesis

The acute response of the liver to hepatotropic viruses involves a direct cytopathic and/or 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 commonly occur. 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 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 these viruses manifests in 3 main functional liver biochemical profiles. These serve as an important guide to diagnosis, 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 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 (PT); 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 because of hepatocyte damage and inflammatory mediators. Elevation of serum alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl transpeptidase levels, mark cholestasis. Absence of cholestatic markers does not rule out progression to chronicity in HCV or HBV infections.

Altered synthetic function is the most important marker of liver injury. Synthetic dysfunction is reflected by a combination of abnormal protein synthesis (prolonged PT, 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). 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.

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 approximately 50% of all clinically apparent acute viral hepatitis in the United States. As a result of aggressive implementation of childhood vaccination programs, the prevalence of symptomatic HAV cases worldwide has declined significantly. However, outbreaks in developing countries and in daycare centers (where the spread of HAV from young, nonicteric, infected children can occur easily) as well as multiple foodborne and waterborne outbreaks have justified the implementation of intensified universal vaccination programs.

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 United States, increased risk of infection is found in contacts with infected persons, childcare centers, and household contacts. Infection is also associated with contact with contaminated food or water and after travel to endemic areas. Common source foodborne and waterborne outbreaks continue to occur, including several caused by 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 approximately 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 fecal 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 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. 385.1 ).

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, leukocytoclastic vasculitis, and cryoglobulinemia can result from circulating immune complexes.

Diagnosis

Acute HAV infection is diagnosed by detecting antibodies to HAV, specifically, anti-HAV (immunoglobulin [Ig] M) by radioimmunoassay or, rarely, by identifying viral particles in stool. A viral polymerase chain reaction (PCR) assay is available for research use ( Table 385.3 ). 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, alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl transpeptidase are almost universally found and do not help to differentiate the cause of hepatitis.

Complications

Although most patients achieve full recovery, distinct complications can occur. ALF from HAV infection is an infrequent complication of HAV. Those at risk for this complication are adolescents and adults, but also immunocompromised patients or those with underlying liver disorders. The height of HAV viremia may be linked to the severity of hepatitis. In the United States, HAV represents <0.5% of pediatric-age ALF; HAV 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 also 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 vitamin supplementation. This syndrome occurs in the absence of any liver synthetic dysfunction and resolves without 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 is prudent 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 approximately 7 days after the onset of jaundice and should be excluded from school, childcare, or work during this period. Careful hand-washing 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 HAV is excellent, with no long-term sequelae. The only feared complication is ALF. Nevertheless, HAV infection remains a major cause of morbidity; it has a high socioeconomic impact during epidemics and in endemic areas.

Etiology

HBV, a member of the Hepadnaviridae family, has a circular, partially double-stranded DNA genome composed of approximately 3,200 nucleotides. Four constitutive genes have been identified: the S (surface), C (core), X, and P (polymer) genes. The surface of the virus includes particles, designated as the hepatitis B surface antigen (HBsAg), which consist of 22 nm diameter spherical particles and 22 nm wide tubular particles with a variable length of up to 200 nm. The inner portion of the virion contains the hepatitis B core antigen (HBcAg), the nucleocapsid that encodes the viral DNA, and a nonstructural antigen called the 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 the 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 their universal vaccination programs. An estimated 1.25 million persons in the United States are chronic HBV carriers, with approximately 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. In fact, in Alaska, where HBV neared epidemic proportions, universal newborn vaccination with mass screening and immunization of susceptible Alaska Natives virtually eliminated symptomatic HBV and secondary hepatocellular carcinoma (HCC).

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, contaminated needles used for acupuncture or tattoos, sexual contact, institutional care, and intimate contact with carriers. No risk factors are identified in approximately 40% of cases. HBV is not thought to be transmitted via indirect exposure, such as sharing toys. After infection, the incubation period ranges from 45-160 days, with a mean of approximately 120 days. 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 HBeAg-positive; up to 90% of these infants become chronically infected if untreated. Additional risk factors include high maternal HBV viral load (HBeAg/HBV DNA titers) and delivery of a prior infant who developed HBV despite appropriate prophylaxis. In most perinatal 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 with hepatitis B immunoglobulin (HBIG) and the HBV immunization, given within 12 hr of delivery, is highly effective in preventing infection and protects >95% of neonates born to HBsAg-positive mothers. Of the 22,000 infants born each year to HBsAg-positive mothers in the United States, >98% receive immunoprophylaxis and are thus protected. Infants who fail to receive the complete vaccination series (e.g., homeless children, international adoptees, and children born outside the United States) have the highest incidence of developing chronic HBV. These and all infants born to HBsAg-positive mothers should have follow-up HBsAg and anti-HBs tested to determine appropriate follow-up. The mothers (HBeAg positive) of these infants who develop chronic HBV infection should receive antiviral therapy during the third trimester for subsequent pregnancies.

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

The risk of developing chronic HBV infection, defined as being positive for HBsAg for longer than 6 mo, is inversely related to age of acquisition. In the United States, although <10% of infections occur in children, these infections account for 20–30% of all chronic cases. This risk of chronic infection is 90% in children younger than 1 yr; the risk is 30% for those 1-5 yr of age and 2% for adults. Chronic HBV infection is associated with the development of chronic liver disease and HCC. 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 10 genotypes (A-J). 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, H in Central America, I in southeast Asia, and J in Japan. Genetic variants have become resistant to some antiviral agents.

Pathogenesis

The acute response of the liver to HBV is similar to that of other 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 noncytopathogenic 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 proteins, make the cell a target for cytotoxic T-cell lysis.

The mechanism for development of chronic hepatitis B is less well understood. To permit hepatocytes to continue to be infected, the core protein or major histocompatibility 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 perinatally acquired cases, resulting in a high incidence of persistent HBV infection in children with no or little inflammation in the liver, normal liver enzymes, and markedly elevated HBV viral load. Although end-stage liver disease rarely develops in those patients, the inherent HCC risk is 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 result in 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 ( Table 385.5 ). 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. 385.2 ).

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, at approximately 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 nodosa, glomerulonephritis, and aplastic anemia. Jaundice is present in approximately 25% of acutely infected patients and usually begins approximately 8 wk after exposure and lasts approximately 4 wk.

In the usual course of resolving HBV infection, symptoms persist 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 development of chronic infection depends largely on the mode and age of acquisition and occurs in up to 90% of perinatally-infected cases. Cirrhosis and HCC 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 has been developed. Most treatments target the immune active phase of the disease, characterized by active inflammation, elevated ALT/AST levels, and progressive fibrosis. Spontaneous HBeAg seroconversion, defined as the development of anti-HBe and loss of HBeAg, 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 perinatally transmitted infections. Seroconversion can occur over many years, during which time significant damage to the liver may take place. There are no large studies that accurately assess the lifetime risks and morbidities of children with chronic HBV infection, making decisions regarding the rationale, efficacy, and timing of still less-than-ideal treatments difficult. Reactivation of chronic infection has been reported in immunosuppressed children treated with chemotherapy, biologic immunomodulators such as infliximab, or T-cell depleting agents, leading to an increased risk of ALF or to rapidly progressing fibrotic liver disease ( Table 385.6 ).