Hepatitis is a general term meaning inflammation of the liver. Microscopically, there is spotty parenchymal cell degeneration, with necrosis of hepatocytes, a diffuse lobular inflammatory reaction, and disruption of liver cell cords. These parenchymal changes are accompanied by reticuloendothelial (Kupffer) cell hyperplasia, periportal infiltration by mononuclear cells, and cell degeneration. Localized areas of necrosis are frequently observed. Later in the course of the disease, there is an accumulation of macrophages near degenerating hepatocytes. Preservation of the reticulum framework allows hepatocyte regeneration so that the highly ordered architecture of the liver lobule can be ultimately regained. The damaged hepatic tissue is usually restored in 8–12 weeks.
Chronic carriers of HBsAg may or may not have demonstrable evidence of liver disease. Persistent (unresolved) viral hepatitis, a mild benign disease that may follow acute hepatitis B in 8–10% of adult patients, is characterized by sporadically abnormal aminotransferase values and hepatomegaly. Histologically, the lobular architecture is preserved, with portal inflammation, swollen and pale hepatocytes (cobblestone arrangement), and slight to absent fibrosis. This lesion is frequently observed in asymptomatic carriers, usually does not progress toward cirrhosis, and has a favorable prognosis.
Chronic active hepatitis features a spectrum of histologic changes from inflammation and necrosis to collapse of the normal reticulum framework with bridging between the portal triads or terminal hepatic veins. HBV is detected in 10–50% of these patients.
Occasionally during acute viral hepatitis, more extensive damage may occur that prevents orderly liver cell regeneration. Such fulminant or massive hepatocellular necrosis is seen in 1–2% of jaundiced patients with hepatitis B. It is 10 times more common in those coinfected with HDV than in the absence of HDV.
Both HBV and HCV have significant roles in the development of hepatocellular carcinoma that may appear many (15–60) years after establishment of chronic infection.
The clinical features of infections by HAV, HBV, and HCV are summarized in Table 35-4. In individual cases, it is not possible to make a reliable clinical distinction among cases caused by the hepatitis viruses.
TABLE 35-4Epidemiologic and Clinical Features of Viral Hepatitis Types A, B, and C ||Download (.pdf) TABLE 35-4 Epidemiologic and Clinical Features of Viral Hepatitis Types A, B, and C
|Feature ||Viral Hepatitis Type A ||Viral Hepatitis Type B ||Viral Hepatitis Type C |
|Incubation period ||10–50 days (average, 25–30) ||50–180 days (average, 60–90) ||15–160 days (average, 50) |
|Principal age distribution ||Children,a young adults ||15–29 years,b babies ||Adultsb |
|Seasonal incidence ||Throughout the year but tends to peak in autumn ||Throughout the year ||Throughout the year |
|Route of infection ||Predominantly fecal–oral ||Predominantly parenteral ||Predominantly parenteral |
|Occurrence of virus || || || |
| Blood ||2 weeks before to ≤1 week after jaundice ||Months to years ||Months to years |
| Stool ||2 weeks before to 2 weeks after jaundice ||Absent ||Probably absent |
| Urine ||Rare ||Absent ||Probably absent |
| Saliva, semen ||Rare (saliva) ||Frequently present ||Present (saliva) |
|Clinical and laboratory features || || || |
| Onset ||Abrupt ||Insidious ||Insidious |
| Fever >38°C (100.4°F) ||Common ||Less common ||Less common |
| Duration of aminotransferase elevation ||1–3 weeks ||1–6+ months ||1–6+ months |
| Immunoglobulins (IgM levels) ||Elevated ||Normal to slightly elevated ||Normal to slightly elevated |
| Complications ||Uncommon, no chronicity ||Chronicity in 5–10% (95% of neonates) ||Chronicity in 70–90% |
| Mortality rate (icteric cases) ||<0.5% ||<1–2% ||0.5–1% |
|Immunity || || || |
| Homologous ||Yes ||Yes ||Probably no |
| Heterologous ||No ||No ||No |
| Duration ||Probably lifetime ||Probably lifetime ||Probably lifetime |
|Immune globulin intramuscular (IG, γ-globulin, ISG) ||Regularly prevents jaundice ||Prevents jaundice only if immune globulin is of sufficient potency against HBV ||Prevents jaundice only if immune globulin is of sufficient potency against HCV |
Other viral diseases that may present as hepatitis are infectious mononucleosis, yellow fever, cytomegalovirus infection, herpes simplex, rubella, and some enterovirus infections. Hepatitis may occasionally occur as a complication of leptospirosis, syphilis, tuberculosis, toxoplasmosis, and amebiasis, all of which are susceptible to specific drug therapy. Noninfectious causes include biliary obstruction, primary biliary cirrhosis, Wilson disease, drug toxicity, and drug hypersensitivity reactions.
In viral hepatitis, onset of jaundice is often preceded by gastrointestinal symptoms such as nausea, vomiting, anorexia, and mild fever. Jaundice may appear within a few days of the prodromal period, but anicteric hepatitis is more common.
Extrahepatic manifestations of viral hepatitis (primarily HBV) include a transient serum sickness-like prodrome consisting of fever, skin rash, and polyarthritis; necrotizing vasculitis (polyarteritis nodosa); and glomerulonephritis. Circulating immune complexes have been suggested as the cause of these syndromes. Diseases associated with chronic HCV infections include mixed cryoglobulinemia and glomerulonephritis. Extrahepatic manifestations are unusual with HAV infections.
Uncomplicated viral hepatitis rarely continues for more than 10 weeks without improvement. Relapses occur in 5–20% of cases and are manifested by abnormalities in liver function with or without the recurrence of clinical symptoms.
The median incubation period is different for each type of viral hepatitis (see Table 35-4). However, there is considerable overlap in timing, and the patient may not know when exposure occurred, so the incubation period is not very useful in determining the specific viral cause.
The onset of disease tends to occur abruptly with HAV (within 24 hours) in contrast to a more insidious onset with HBV and HCV. Complete recovery occurs in most hepatitis A cases (Table 35-5). The disease is more severe in adults than in children, in whom it often goes unnoticed. Relapses of HAV infection can occur 1–4 months after initial symptoms have resolved.
TABLE 35-5Outcomes of Infection With Hepatitis A Virusa ||Download (.pdf) TABLE 35-5 Outcomes of Infection With Hepatitis A Virusa
|Outcome ||Children ||Adults |
|Inapparent (subclinical) infection (%) ||80–95 ||10–25 |
|Icteric disease (%) ||5–20 ||75–90 |
|Complete recovery (%) ||>98 ||>98 |
|Chronic disease (%) ||None ||None |
|Mortality rate (%) ||0.1 ||0.3–2.1 |
The outcome after infection with HBV varies, ranging from complete recovery to progression to chronic hepatitis and, rarely, death from fulminant disease. In adults, 65–80% of infections are inapparent, with 90–95% of all patients recovering completely. In contrast, 80–95% of infants and young children infected with HBV become chronic carriers (Table 35-6), and their serum remains positive for HBsAg. The vast majority of individuals with chronic HBV remain asymptomatic for many years; there may or may not be biochemical and histologic evidence of liver disease. Chronic carriers are at high risk of developing hepatocellular carcinoma.
TABLE 35-6Transmission of Hepatitis B Virus and Spectrum of Outcomes of Infection ||Download (.pdf) TABLE 35-6 Transmission of Hepatitis B Virus and Spectrum of Outcomes of Infection
|Feature ||Transmissiona |
|Vertical (Asia) ||Contact (Africa) ||Parenteral, Sexual |
|Age at infection ||Newborns, infants ||Young children ||Teenagers, adults |
|Recovery from acute infection (%) ||5 ||20 ||90–95 |
|Progression to chronic infection (%) ||95 ||80 ||5–10 |
|Chronic carriersb (% of total population) ||10–20 ||10–20 ||0.5 |
Fulminant hepatitis occasionally develops during acute viral hepatitis, defined as hepatic encephalopathy within the first 8 weeks of disease in patients without preexisting liver disease. It is fatal in 70–90% of cases, with survival uncommon after the age of 40 years. Fulminant HBV disease is associated with superinfection by other agents, including HDV. Most patients who survive have complete restoration of the hepatic parenchyma with normal liver function after recovery. Fulminant disease rarely occurs with HAV or HCV infections.
Hepatitis C is usually clinically mild, with only minimal to moderate elevation of liver enzymes. Hospitalization is unusual, and jaundice occurs in fewer than 25% of patients. Despite the mild nature of the disease, 70–90% of cases progress to chronic liver disease. Most patients are asymptomatic, but histologic evaluation often reveals evidence of chronic active hepatitis, especially in those whose disease is acquired after transfusion. Many patients (20–50%) develop cirrhosis and are at high risk for hepatocellular carcinoma (5–25%) decades later. About 40% of chronic liver disease is HCV related, resulting in an estimated 8000–10,000 deaths annually in the United States. End-stage liver disease associated with HCV is the most frequent indication for adult liver transplants.
Liver biopsy permits a tissue diagnosis of hepatitis. Tests for abnormal liver function, such as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin, supplement the clinical, pathologic, and epidemiologic findings.
The clinical, virologic, and serologic events after exposure to HAV are shown in Figure 35-7. Virus particles have been detected by immune electron microscopy in fecal extracts of hepatitis A patients (see Figure 35-1). Virus appears early in the disease and disappears within 2 weeks after the onset of jaundice.
Immunologic and biologic events associated with human infection with hepatitis A virus. IgG, immunoglobulin G; IgM, immunoglobulin M. (Reproduced from Hollinger FB, Ticehurst JR: Hepatitis A virus. In Fields BN, Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 3rd ed. Lippincott-Raven, 1996. Modified with permission from Hollinger FB, Dienstag JL: Hepatitis viruses. In Lennette EH [editor]. Manual of Clinical Microbiology, 4th ed. American Society for Microbiology, 1985.)
HAV can be detected in the liver, stool, bile, and blood of naturally infected humans and experimentally infected nonhuman primates by immunoassays, nucleic acid hybridization assays, or PCR. HAV is detected in the stool from about 2 weeks before the onset of jaundice up to 2 weeks after.
Anti-HAV appears in the immunoglobulin M (IgM) fraction during the acute phase, peaking about 2 weeks after elevation of liver enzymes (Table 35-7). Anti-HAV IgM usually declines to nondetectable levels within 3–6 months. Anti-HAV IgG appears soon after the onset of disease and persists for decades. Thus, detection of IgM-specific anti-HAV in the blood of an acutely infected patient confirms the diagnosis of hepatitis A. Enzyme-linked immunosorbent assay is the method of choice for measuring HAV antibodies.
TABLE 35-7Interpretation of Hepatitis A, C, and D Virus Serologic Markers in Patients With Hepatitis ||Download (.pdf) TABLE 35-7 Interpretation of Hepatitis A, C, and D Virus Serologic Markers in Patients With Hepatitis
|Assay Results ||Interpretation |
|Anti-HAV IgM positive ||Acute infection with HAV |
|Anti-HAV IgG positive ||Past infection with HAV |
|Anti-HCV positive ||Current or past infection with HCV |
|Anti-HD positive, HBsAg positive ||Infection with HDV |
|Anti-HD positive, anti-HBc IgM positive ||Coinfection with HDV and HBV |
|Anti-HD positive, anti-HBc IgM negative ||Superinfection of chronic HBV infection with HDV |
Clinical and serologic events after exposure to HBV are depicted in Figure 35-8 and summarized in Table 35-8. DNA polymerase activity, HBV DNA, and HBeAg, which are representative of the viremic stage of hepatitis B, occur early in the incubation period, concurrently or shortly after the first appearance of HBsAg. High concentrations of HBV particles may be present in the blood (up to 1010 particles/mL) during the initial phase of infection; communicability is highest at this time. HBsAg is usually detectable 2–6 weeks in advance of clinical and biochemical evidence of hepatitis and persists throughout the active course of the disease. Disappearance of HBsAg is thought to be associated with recovery from infection, but some patients continue to have occult HBV infection with detectable HBV DNA and can still transmit virus.
Clinical and serologic events occurring in a patient with acute hepatitis B virus infection. The common diagnostic tests and their interpretation are presented in Table 35-8. ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgG, immunoglobulin G; IgM, immunoglobulin M. (Reproduced with permission from Hollinger FB, Dienstag JL: Hepatitis B and D viruses. In Murray PR [editor]. Manual of Clinical Microbiology, 7th ed. Washington DC: ASM Press, 1999. ©1999 American Society for Microbiology. No further reproduction or distribution is permitted without the prior written permission of American Society for Microbiology.)
TABLE 35-8Interpretation of Hepatitis B Virus Serologic Markers in Patients With Hepatitisa ||Download (.pdf) TABLE 35-8 Interpretation of Hepatitis B Virus Serologic Markers in Patients With Hepatitisa
|Assay Results ||Interpretation |
|HBsAg ||Anti-HBs ||Anti-HBc |
|Positive ||Negative ||Negative ||Early acute HBV infection. Confirmation is required to exclude nonspecific reactivity. |
|Positive ||(±) ||Positive ||HBV infection, either acute or chronic. Differentiate with IgM anti-HBc. Determine level of replicative activity (infectivity) with HBeAg or HBV DNA. |
|Negative ||Positive ||Positive ||Indicates previous HBV infection and immunity to hepatitis B. |
|Negative ||Negative ||Positive ||Possibilities include HBV infection in remote past; “low-level” HBV carrier; “window” between disappearance of HBsAg and appearance of anti-HBs; or false-positive or nonspecific reaction. Investigate with IgM anti-HBc and HBV DNA. When present, anti-HBe helps validate the anti-HBc reactivity. |
|Negative ||Negative ||Negative ||Never infected with HBV. Possibilities for liver injury include another infectious agent, toxic injury to the liver, disorder of immunity, hereditary disease of the liver, or disease of the biliary tract. |
|Negative ||Positive ||Negative ||Successful vaccine response to HBV immunization. |
High levels of IgM-specific anti-HBc are frequently detected at the onset of clinical illness. Because this antibody is directed against the 27-nm internal core component of HBV, its appearance in the serum is indicative of viral replication. Antibody to HBsAg is first detected at a variable period after the disappearance of HBsAg. It is present in low concentrations. Before HBsAg disappears, HBeAg is replaced by anti-HBe, signaling the start of resolution of the disease. However, some patients can develop HBeAg-negative chronic hepatitis with pre-core HBV mutants, usually associated with a stop codon mutation at nucleotide 1896 that results in absent HBeAg production but with continued viral progression.
By definition, HBV chronic carriers are those in whom HBsAg persists for more than 6 months in the presence of HBeAg or anti-HBe. HBsAg may persist for years after loss of HBeAg. In contrast to the high titers of IgM-specific anti-HBc observed in acute disease, low titers of IgM anti-HBc are found in the sera of most chronic HBsAg carriers. Small amounts of HBV DNA are usually detectable in the serum as long as HBsAg is present.
The most useful detection methods are enzyme-linked immunosorbent assay for HBV antigens and antibodies and PCR for viral DNA.
Clinical and serologic events associated with HCV infections are shown in Figure 35-9. Most primary infections are asymptomatic or clinically mild (20–30% have jaundice; 10–20% have only nonspecific symptoms such as anorexia, malaise, and abdominal pain). Serologic assays are available for diagnosis of HCV infection. Enzyme immunoassays detect antibodies to HCV but do not distinguish among acute, chronic, or resolved infection (see Table 35-7). Anti-HCV antibodies can be detected in 50–70% of patients at the onset of symptoms, but in others, antibody appearance is delayed 3–6 weeks. Antibodies are directed against core, envelope, and NS3 and NS4 proteins and tend to be relatively low in titer. Nucleic acid-based assays (eg, reverse transcription PCR) detect the presence of circulating HCV RNA and are useful for diagnosis of acute infection soon after exposure and for monitoring patients on antiviral therapy. Nucleic acid assays also are used to genotype HCV isolates.
Clinical and serologic events associated with hepatitis C virus (HCV) infection. ALT, alanine aminotransferase; anti-HCV, antibody to HCV; HCC, hepatocellular carcinoma. (Reproduced with permission from Garnier L, Inchauspé G, Trépo C: Hepatitis C virus. In Richman DD, Whitley RJ, Hayden FG [editors]. Clinical Virology, 2nd ed. ASM Press, 2002. Washington, DC. ©2002 American Society for Microbiology. No further reproduction or distribution is permitted without the prior written permission of American Society for Microbiology.)
Serologic patterns after HDV infection are shown in Figure 35-10 and listed in Table 35-7. Because HDV depends on a coexistent HBV infection, acute type D infection occurs either as a simultaneous infection (coinfection) with HBV or as a superinfection of a person chronically infected with HBV. In the coinfection pattern, antibody to HDAg develops late in the acute phase of infection and may be of low titer. Assays for HDAg or HDV RNA in the serum or for IgM-specific anti-HDV are preferable. All markers of HDV replication disappear during convalescence; even the HDV antibodies may disappear within months to years. However, superinfection by HDV usually results in persistent HDV infection (> 70% of cases). High levels of both IgM and IgG anti-HD persist, as do levels of HDV RNA and HDAg. HDV superinfections may be associated with fulminant hepatitis.
Serologic patterns of type D hepatitis after coinfection or superinfection of a person with hepatitis B virus (HBV) infection. Top: Coexistent acute hepatitis B and hepatitis D. Middle: Acute hepatitis D superimposed on a chronic HBV infection. Bottom: Acute hepatitis D progressing to chronic hepatitis, superimposed on a chronic HBV infection. ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HD, antibody to delta antigen; HBsAg, hepatitis B surface antigen; HDAg, delta antigen; HDV, hepatitis D virus; IgG, immunoglobulin G; IgM, immunoglobulin M. (Reproduced with permission from Purcell RH et al: Hepatitis. In Schmidt NJ, Emmons RW [editors]. Diagnostic Procedures for Viral, Rickettsial and Chlamydial Infections, 6th ed. American Public Health Association, 1989.)
Currently, there is evidence for five hepatitis viruses—types A, B, C, D, and E. A single infection with any is believed to confer homologous but not heterologous protection against reinfection. A possible exception may be HCV; reinfection with HCV may occur.
Most cases of hepatitis type A presumably occur without jaundice during childhood, and by late adulthood there is a widespread resistance to reinfection. However, serologic studies in the United States and several Asian countries indicate that the incidence of infection may be declining as a result of improvements in sanitation commensurate with a rise in the standard of living coupled with expanded use of the vaccine in some countries. It has been estimated that as many as 60–90% of young middle- to upper-income adults in the United States may be susceptible to type A hepatitis.
Infection with HBV of a specific subtype (eg, HBsAg/adw) appears to confer immunity to other HBsAg subtypes, probably because of their common group a specificity. The immunopathogenetic mechanisms that result in viral persistence and hepatocellular injury in type B hepatitis remain to be elucidated. As the virus is not cytopathic, it is believed that hepatocellular injury during acute disease represents a host immune attack against HBV-infected hepatocytes.
Host responses, both immunologic and genetic, have been proposed to account for the frequency of HBV chronicity in those infected as infants. About 95% of newborns infected at birth become chronic carriers of the virus, often for life (see Table 35-6). This risk decreases steadily with time, so that the risk of infected adults becoming carriers decreases to 10%. Hepatocellular carcinoma is most likely to occur in adults who experienced HBV infection at a very early age and became carriers. Therefore, for vaccination to be maximally effective against the carrier state, cirrhosis, and hepatoma, it must be carried out during the first week of life.
HCV genotypes 1–4 are the predominant types circulating in Western countries and display some differential characteristics. Genotype 1 is predominant in North America, Japan, and Western Europe. It shows the poorest response to interferon (IFN) therapy and may have a more deleterious effect on the progression of human immunodeficiency virus (HIV) type 1 disease than other HCV genotypes. In contrast, HCV genotype 2 responds the best to IFN-based therapies. Genotype 3 shows the highest rate of spontaneous clearance, and genotype 4 seems to have the highest frequency leading to chronic infection after acute infection.
Less is known about host immune responses to HCV. The majority of acute infections are asymptomatic or mild, and chronic infections usually progress slowly and insidiously. It appears that the immune response is slow to develop and relatively weak, reflecting the fact that HCV has particularly effective immune evasion mechanisms.
The global distributions of hepatitis A, B, and C infections are shown in Figure 35-11. There are marked differences in the epidemiologic features of these infections (see Table 35-4).
Global distribution of hepatitis viruses causing human disease. A: Hepatitis A virus. B: Hepatitis B virus. (Source: World Health Organization, 2011.) C: Hepatitis C virus. (Source: World Health Organization, 2001.)
The risk of these viruses being transmitted by transfusion today in the United States is markedly reduced as a result of improved screening tests, including nucleic acid testing and the establishment of volunteer donor populations. It was calculated in 2012 that the risk of transmission of HBV by blood transfusion was one in 1.7 million and for HCV was one in 6–7 million donations.
HAV is widespread throughout the world. Outbreaks of type A hepatitis are common in families and institutions, summer camps, day care centers, neonatal intensive care units, and among military troops. The most likely mode of transmission under these conditions is by the fecal–oral route through close personal contact. Stool specimens may be infectious for up to 2 weeks before to 2 weeks after onset of jaundice.
Under crowded conditions and poor sanitation, HAV infections occur at an early age; most children in such circumstances become immune by age 10 years. Clinical illness is uncommon in infants and children; disease is most often manifest in children and adolescents, with the highest rates in those between 5 and 14 years of age. The ratio of anicteric to icteric cases in adults is about one to three; in children, it may be as high as 12 to one. However, fecal excretion of HAV antigen and RNA persists longer in the young than in adults.
Recurrent epidemics are a prominent feature. Sudden, explosive epidemics of type A hepatitis usually result from fecal contamination of a single source (eg, drinking water, food, or milk). The consumption of raw oysters or improperly steamed clams obtained from water polluted with sewage has also resulted in several outbreaks of hepatitis A. The largest outbreak of this type occurred in Shanghai in 1988, when more than 300,000 cases of hepatitis A were attributed to uncooked clams from polluted water. A multistate foodborne outbreak that was traced to frozen strawberries occurred in the United States in 1997.
Other identified sources of potential infection are nonhuman primates. There have been more than 35 outbreaks in which primates, usually chimpanzees, have infected humans in close personal contact with them.
HAV is seldom transmitted by the use of contaminated needles and syringes or through the administration of blood. Transfusion-associated hepatitis A is rare because the viremic stage of infection occurs during the prodromal phase and is of short duration, the titer of virus in the blood is low, and there is no carrier state. However, a 1996 report documented the transmission of HAV to individuals with hemophilia through clotting factor concentrates. There is little evidence for HAV transmission by exposure to urine or nasopharyngeal secretions of infected patients. Hemodialysis plays no role in the spread of hepatitis A infections to either patients or staff.
In the United States in the prevaccine era, there were an estimated 271,000 infections per year. Since the advent of hepatitis A vaccines, infection rates have declined sharply to an estimated 2700 cases in 2011.
Groups that are at increased risk of acquiring hepatitis A are travelers to developing countries from developed countries, men who have sex with men, users of injection and noninjection drugs, persons with clotting factor disorders, and persons working with nonhuman primates. Individuals with chronic liver disease are at increased risk for fulminant hepatitis if a hepatitis A infection occurs. These groups should be vaccinated.
HBV is worldwide in distribution. Transmission modes and response to infection vary, depending on the age at time of infection (Table 35-6). Most individuals infected as infants develop chronic infections. As adults, they are subject to liver disease and are at high risk of developing hepatocellular carcinoma. There are more than 350 million carriers, of whom about 1 million live in the United States; 25% of carriers develop chronic active hepatitis. Worldwide, about 600,000 deaths a year are attributed to HBV-related liver disease and hepatocellular carcinoma.
There is a high burden of HBV infections among HIV-infected persons, with a 36% prevalence in 2008 in the United States.
The major modes of HBV transmission during infancy are from an infected mother to her newborn during delivery and from an infected household contact to an infant.
There is no seasonal trend for HBV infection and no high predilection for any age group, although there are definite high-risk groups such as parenteral drug abusers, institutionalized persons, health care personnel, multiply transfused patients, organ transplant patients, hemodialysis patients and staff, highly promiscuous persons, and newborn infants born to mothers with hepatitis B. Mandatory screening of blood donors for markers of HBV infection (HBsAg, HBc Ab, and HBV DNA) has substantially reduced the number of cases of transfusion-associated hepatitis. People have been infected by improperly sterilized syringes, needles, or scalpels and even by tattooing or ear piercing.
Other modes of transmission of hepatitis B exist. HBsAg can be detected in saliva, nasopharyngeal washings, semen, menstrual fluid, and vaginal secretions as well as in blood. Transmission from carriers to close contacts by the oral route or by sexual or other intimate exposure occurs. There is strong evidence of transmission from persons with subclinical cases and carriers of HBsAg to homosexual and heterosexual long-term partners. Transmission by the fecal–oral route has not been documented. Recalling that there may be more than 1 billion virions/mL of blood from an HBeAg-positive carrier and that the virus is resistant to drying, it should be assumed that all bodily fluids from HBV-infected patients may be infectious. Subclinical infections are common, and these unrecognized infections represent the principal hazard to hospital personnel.
Health care personnel (medical and dental surgeons, pathologists, other physicians, nurses, laboratory technicians, and blood bank personnel) have a higher incidence of hepatitis and prevalence of detectable HBsAg or anti-HBs than those who have no occupational exposure to patients or blood products. The risk that these apparently healthy HBsAg carriers (especially medical and dental surgeons) represent to the patients under their care remains to be determined but is probably small.
Hepatitis B infections are common among patients and staff of hemodialysis units. As many as 50% of the renal dialysis patients who contract hepatitis B may become chronic carriers of HBsAg compared with 2% of the staff group, emphasizing differences in the host immune response. Family contacts are also at increased risk.
The incubation period of hepatitis B is 50–180 days, with a mean between 60 and 90 days. It appears to vary with the dose of HBV administered and the route of administration, being prolonged in patients who receive a low dose of virus or who are infected by a nonpercutaneous route.
Infections by HCV are extensive throughout the world. The World Health Organization estimates that about 3% of the world population has been infected, with population subgroups in Africa having prevalence rates as high as 10%. Other high-prevalence areas are found in South America and Asia. It is estimated that there are more than 170 million chronic carriers worldwide who are at risk of developing liver cirrhosis, liver cancer, or both—and that more than 3 million of them are in the United States.
HCV is transmitted primarily through direct percutaneous exposures to blood, although in 10–50% of cases, the source of HCV cannot be identified. In roughly decreasing order of prevalence of infection are injecting drug users (~80%), individuals with hemophilia treated with clotting factor products before 1987, recipients of transfusions from HCV-positive donors, chronic hemodialysis patients (10%), persons who engage in high-risk sexual practices, and health care workers (1%). The virus can be transmitted from mother to infant, although not as frequently as for HBV. Estimates of mother-to-child vertical transmission vary from 3% to 10%. Mothers with higher HCV viral loads or coinfection with HIV more frequently transmit HCV. No risk of transmission has been associated with breastfeeding.
HCV was found in saliva from more than one-third of patients with HCV and HIV coinfections. HCV has been transmitted by commercial intravenous immune globulin (IG) preparations, including an outbreak in the United States in 1994. The population of Egypt has a high prevalence of HCV (~20%), where transmission has been linked to an attempt (from the 1950s to 1980s) to treat the parasitic disease schistosomiasis by therapy that involved multiple injections, often with improperly sterilized or reused needles. HCV infection has been associated with tattooing and, in some countries, with folk medicine practices. HCV can be transmitted to an organ transplant recipient from an HCV-positive donor.
The average incubation period for HCV is 6–7 weeks. The average time from exposure to seroconversion is 8–9 weeks, and about 90% of patients are anti-HCV positive within 5 months.
D. Hepatitis D (Delta Agent)
HDV is found throughout the world but with a nonuniform distribution. Its highest prevalence has been reported in Italy, the Middle East, central Asia, West Africa, and South America. HDV infects all age groups. Persons who have received multiple transfusions, intravenous drug abusers, and their close contacts are at high risk.
The primary routes of transmission are believed to be similar to those of HBV, although HDV does not appear to be a sexually transmitted disease. Infection depends on HBV replication because HBV provides an HBsAg envelope for HDV. The incubation period varies from 2 to 12 weeks, being shorter in HBV carriers who are superinfected with the agent than in susceptible persons who are simultaneously infected with both HBV and HDV. HDV has been transmitted perinatally, but fortunately, it is not prevalent in regions of the world (eg, Asia) where perinatal transmission of HBV occurs frequently.
Two epidemiologic patterns of delta infection have been identified. In Mediterranean countries, delta infection is endemic among persons with hepatitis B, and most infections are thought to be transmitted by intimate contact. In nonendemic areas, such as the United States and northern Europe, delta infection is confined to persons exposed frequently to blood and blood products, primarily intravenous drug users and individuals with hemophilia.
Delta hepatitis may occur in explosive outbreaks and affect entire localized pockets of hepatitis B carriers. Outbreaks of severe, often fulminant and chronic delta hepatitis have occurred for decades in isolated populations in the Orinoco and Amazon basins of South America. In the United States, HDV has been found to participate in 20–30% of cases of chronic hepatitis B, acute exacerbations of chronic hepatitis B, and fulminant hepatitis B, and 3–12% of blood donors with serum HBsAg have antibodies to HDV. Delta hepatitis is not a new disease because globulin lots prepared from plasma collected in the United States more than 40 years ago contain antibodies to HDV.
Treatment of patients with hepatitis A, D, and E is supportive and directed at allowing hepatocellular damage to resolve and repair itself. HBV and HCV have specific treatments, with some patients achieving viral clearance, known as sustained virologic response (see Table 30-7).
Treatment of HBV infection is recommended for patients with chronic active hepatitis to prevent progression of liver fibrosis and development of hepatocellular carcinoma. Pegylated interferon alfa-2a, entecavir, and tenofovir are first-line therapies for hepatitis B. Resistance testing can indicate specific viral mutations that influence choice of therapy. Interferon treatment can lead to approximately 25% rate of loss of HBV DNA. Entecavir is a guanosine analogue inhibitor of HBV polymerase, with treatment leading to 67% undetectable HBV DNA in HBeAg-positive patients and 90% undetectable HBV DNA in HBeAg-negative patients. Tenofovir in a nucleotide analogue inhibitor of HBV reverse transcriptase and polymerase, with response rates of 76% and 93% in HBeAg-positive and HBeAg-negative patients, respectively. At 5 years of therapy, these rates decreased to 83–65%, respectively.
Telbivudine is a cytosine nucleoside analogue that is a second-line therapy agent and inhibitor of HBV DNA polymerase. Lamivudine, also known as 3TC, and adefovir are nucleoside analog viral polymerase inhibitors that are third-line agents for therapy. Continual progress is being made in HBV treatment, and further approved drugs are expected to be available in the future. For patients with HIV and HBV coinfection, drugs may be chosen to target both pathogens simultaneously.
Pegylated interferon combined with ribavirin has been the standard treatment for chronic hepatitis C. The likelihood of patients achieving sustained virologic response depends on several factors, including patient age, viral load, degree of liver fibrosis, HCV genotype, and patient IL28B receptor polymorphism. Genetic markers of poor prognosis are HCV genotype 1 and the human TT polymorphism in IL28B at rs12979860. Antiviral therapy is given for 24 or 48 weeks, depending on the viral genotype, with cessation of therapy if sustained virologic response is unlikely to be achieved. This classical therapy leads to sustained virologic response in 30–35% of HCV genotype 1 patients and 75–80% of genotype 2 or 3 patients.
Major improvements in HCV treatment have been obtained with first-generation protease inhibitor drugs telaprevir and boceprevir. These target the viral protease, which cleaves the translated viral polypeptide into functional proteins. They are given for HCV genotype 1 infections in combination with interferon and ribavirin, and showed approximately 60–80% sustained virologic response rates, even in patients who failed prior treatment. However, these drugs are quite toxic and selected viral resistance is a concern.
Second-generation HCV antivirals have recently been approved for use based on clinical trials showing more than 90% sustained virologic response. Sofosbuvir is a nucleotide analog HCV viral RNA polymerase inhibitor and simepravir is an HCV protease inhibitor. These drugs have less toxicity than first-generation antivirals, and greater efficacy. Studies are ongoing to determine the effect of specific viral mutations on drug efficacy. Interferon-free treatment regimens are currently being evaluated to reduce the overall toxicity of therapy and are expected to be available shortly.
Orthotopic liver transplantation is a treatment for chronic hepatitis B and C end-stage liver damage. However, the risk of reinfection on the graft is at least 80% with HBV and 50% with HCV, presumably from extrahepatic reservoirs in the body. Because donor livers are in such short supply, HBV- or HCV-positive livers may be transplanted into seropositive recipients with end-stage liver disease.
Viral vaccines and protective IG preparations are available against HAV and HBV. Neither type of reagent is currently available to prevent HCV infections.
Simple environmental procedures can limit the risk of infection to health care workers, laboratory personnel, and others. With this approach, all blood and body fluids and materials contaminated with them are treated as if they are infectious for HIV, HBV, HCV, and other bloodborne pathogens. Exposures that might place workers at risk of infection include percutaneous injury (eg, needlestick) or contact of mucous membrane or nonintact skin (eg, chapped, cuts, dermatitis) with blood, tissue, or other body fluids that are potentially infectious. Methods are devised to prevent contact with such samples. Examples of specific precautions include the following: Gloves should be used when handling all potentially infectious materials; protective garments should be worn and removed before leaving the work area; masks and eye protection should be worn whenever splashes or droplets from infectious material pose a risk; only disposable needles should be used; needles should be discarded directly into special containers without resheathing; work surfaces should be decontaminated using a bleach solution; and laboratory personnel should refrain from mouth pipetting, eating, drinking, and smoking in the work area. Metal objects and instruments can be disinfected by autoclaving or by exposure to ethylene oxide gas.
Formalin-inactivated HAV vaccines made from cell culture-adapted virus were licensed in the United States in 1995. The vaccines are safe, effective, and recommended for use in persons more than 1 year of age.
Routine vaccination of all children is now recommended, as is vaccination of persons at increased risk, including international travelers, men who have sex with men, and drug users.
Until all susceptible at-risk groups are immunized, prevention and control of hepatitis A still must emphasize interrupting the chain of transmission and using passive immunization.
The appearance of hepatitis in camps or institutions is often an indication of poor sanitation and poor personal hygiene. Control measures are directed toward the prevention of fecal contamination of food, water, or other sources by the individual. Reasonable hygiene—such as handwashing, the use of disposable plates and eating utensils, and the use of 0.5% sodium hypochlorite (eg, 1:10 dilution of chlorine bleach) as a disinfectant—is essential in preventing the spread of HAV during the acute phase of the illness.
Immune (γ) globulin (IG) is prepared from large pools of normal adult plasma and confers passive protection in about 90% of those exposed when given within 1–2 weeks after exposure to hepatitis A. Its prophylactic value decreases with time, and its administration more than 2 weeks after exposure or after onset of clinical symptoms is not indicated. In the doses generally prescribed, IG does not prevent infection but rather makes the infection mild or subclinical and permits active immunity to develop. HAV vaccine produces a more enduring immunity and should replace the use of IG.
A vaccine for hepatitis B has been available since 1982. The initial vaccine was prepared by purifying HBsAg associated with the 22-nm particles from healthy HBsAg-positive carriers and treating the particles with virus-inactivating agents (formalin, urea, heat). Preparations containing intact 22-nm particles have been highly effective in reducing HBV infection. Although plasma-derived vaccines are still in use in certain countries, they have been replaced in the United States by recombinant DNA-derived vaccines. These vaccines consist of HBsAg produced by a recombinant DNA in yeast cells or in continuous mammalian cell lines. The HBsAg expressed in yeast forms particles 15–30 nm in diameter, with the morphologic characteristics of free surface antigen in plasma, although the polypeptide antigen produced by recombinant yeast is not glycosylated. The vaccine formulated using this purified material has a potency similar to that of vaccine made from plasma-derived antigen.
Preexposure prophylaxis with a commercially available hepatitis B vaccine currently is recommended by the World Health Organization, the Centers for Disease Control and Prevention, and the Advisory Committee on Immunization Practices for all susceptible, at-risk groups. In the United States, HBV vaccine is recommended for all children as part of their regular immunization schedule.
Hepatitis B vaccination is the most effective measure to prevent HBV and its consequences. A comprehensive public health strategy exists to eliminate HBV transmission in the United States. It involves universal vaccination of infants, routine screening of all pregnant women for HBsAg, postexposure immunoprophylaxis of infants born to HBsAg-positive mothers, vaccination of children and adolescents not previously vaccinated, and vaccination of unvaccinated adults at increased risk for infection.
Immunosuppressed groups (eg, hemodialysis patients, and those receiving cancer chemotherapy or infected with HIV) respond to vaccination less well than healthy individuals.
Studies on passive immunization using specific hepatitis B immune globulin (HBIG) have shown a protective effect if it is given soon after exposure. HBIG is not recommended for preexposure prophylaxis because the HBV vaccine is available and effective. Persons exposed to HBV percutaneously or by contamination of mucosal surfaces should immediately receive both HBIG and HBsAg vaccine administered simultaneously at different sites to provide immediate protection with passively acquired antibody followed by active immunity generated by the vaccine.
IG isolated from plasma by the cold ethanol fractionation method has not been documented to transmit HBV, HAV, HCV, or HIV in the United States. IGs prepared outside the United States by other methods have been implicated in outbreaks of hepatitis B and C.
Women who are HBV carriers or who acquire type B hepatitis while pregnant can transmit the disease to their infants. The effectiveness of hepatitis vaccine and HBIG in preventing hepatitis B in infants born to HBV-positive mothers has been substantiated. Reduction in the cost of vaccine for public health programs has made vaccination of newborns feasible in areas of high endemicity. The high cost of HBIG precludes its use in most countries.
Patients with acute type B hepatitis generally need not be isolated as long as blood and instrument precautions are stringently observed, both in the general patient care areas and in the laboratories. Because spouses and intimate contacts of persons with acute type B hepatitis are at risk of acquiring clinical type B hepatitis, they need to be informed about practices that might increase the risk of infection or transmission. There is no evidence that asymptomatic HBsAg-positive food handlers pose a health risk to the general public.
There is no vaccine for hepatitis C although several candidate vaccines are undergoing tests. Control measures focus on prevention activities that reduce risks for contracting HCV. These include screening and testing blood, plasma, organ, tissue, and semen donors; virus inactivation of plasma-derived products; counseling of persons with high-risk drug or sexual practices; implementation of infection control practices in health care and other settings; and professional and public education.
Delta hepatitis can be prevented by vaccinating HBV-susceptible persons with hepatitis B vaccine. However, vaccination does not protect hepatitis B carriers from superinfection by HDV.