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InternalMed_Harrison. liver injury and progressive fibrosis emerge during later decades (the so-called immunoreactive, or immunointolerant, phase), the level of immunologic tolerance to HBV remains substantial. More accurately, in patients with neonatally acquired HBV infection, a dynamic equilibrium exists between tolerance and intolerance, the outcome of which determines the clinical expression of chronic infection. Persons infected as neonates tend to have a relatively higher level of immunologic tolerance during the early decades of life and a relatively lower level (but only rarely a loss) of tolerance in the later decades of life.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis C Cell-mediated immune responses and elaboration by T cells of antiviral cytokines contribute to the multicellular innate and adaptive immune responses involved in the containment of infection and pathogenesis of liver injury associated with hepatitis C. The fact that HCV is so efficient in evading these immune mechanisms is a testament to its highly evolved ability to disrupt host immune responses at multiple levels. After exposure to HCV, the host cell identifies viral 2011 product motifs (pattern recognition receptors) that distinguish the virus from “self,” resulting in the elaboration of interferons and other cytokines that result in activation of innate and adaptive immune responses. Intrahepatic HLA class I restricted cytolytic T cells directed at nucleocapsid, envelope, and nonstructural viral protein antigens have been demonstrated in patients with chronic hepatitis C; however, such virus-specific cytolytic T cell responses do not correlate adequately with the


InternalMed_Harrison

InternalMed_Harrison. and nonstructural viral protein antigens have been demonstrated in patients with chronic hepatitis C; however, such virus-specific cytolytic T cell responses do not correlate adequately with the degree of liver injury or with recovery. Yet, a consensus has emerged supporting a role in the pathogenesis of HCV-associated liver injury of virus-activated CD4+ helper T cells that stimulate, via the cytokines they elaborate, HCV-specific CD8+ cytotoxic T cells. These responses appear to be more robust (higher in number, more diverse in viral antigen specificity, more functionally effective, and more long lasting) in those who recover from HCV than in those who have chronic infection. Contributing to chronic infection are a CD4+ proliferative defect that results in rapid contraction of CD4+ responses, mutations in CD8+ T cell–targeted viral epitopes that allow HCV to escape immune-mediated clearance, and upregulation of inhibi tory receptors on functionally impaired, exhausted T cells.


InternalMed_Harrison

InternalMed_Harrison. responses, mutations in CD8+ T cell–targeted viral epitopes that allow HCV to escape immune-mediated clearance, and upregulation of inhibi tory receptors on functionally impaired, exhausted T cells. Although attention has focused on adaptive immunity, HCV proteins have been shown to interfere with innate immunity by resulting in blocking of type 1 interferon responses and inhibition of interferon signaling and effector molecules in the interferon signaling cascade. Several HLA alleles have been linked with self-limited hepatitis C, the most convincing of which is the CC haplotype of the IL28B gene, which codes for interferon λ3, a component of innate immune antiviral defense. The IL28B association is even stronger when combined with HLA class II DQB1*03:01. The link between non-CC IL28B polymorphisms and failure to clear HCV infection has been explained by a chromosome 19q13.13 frameshift variant upstream of IL28B, the ΔG polymorphism of which creates an ORF in a novel interferon gene


InternalMed_Harrison

InternalMed_Harrison. and failure to clear HCV infection has been explained by a chromosome 19q13.13 frameshift variant upstream of IL28B, the ΔG polymorphism of which creates an ORF in a novel interferon gene (IFN-λ4) associated with impaired HCV clearance. Also shown to contribute to limiting HCV infection are NK cells of the innate immune system that function when HLA class I molecules required for successful adaptive immunity are underexpressed. Both peripheral and intrahepatic NK cell cytotoxicity are dysfunctional in persistent HCV infection. Adding to the complexity of the immune response, HCV core, NS4B, and NS5B have been shown to suppress the immunoregulatory nuclear factor (NF)-κB pathway, resulting in reduced antiapoptotic proteins and a resultant increased vulnerability to tumor necrosis factor (TNF) α–mediated cell death. Patients with hepatitis C and unfavorable (non-CC, associated with reduced HCV clearance) IL28B alleles have been shown to have depressed NK cell/innate immune function. Of


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InternalMed_Harrison. α–mediated cell death. Patients with hepatitis C and unfavorable (non-CC, associated with reduced HCV clearance) IL28B alleles have been shown to have depressed NK cell/innate immune function. Of note, the emergence of substantial viral quasispecies diversity and HCV sequence variation allow the virus to evade attempts by the host to contain HCV infection by both humoral and cellular immunity.


InternalMed_Harrison

InternalMed_Harrison. Finally, cross-reactivity between viral antigens (HCV NS3 and NS5A) and host autoantigens (cytochrome P450 2D6) has been invoked to explain the association between hepatitis C and a subset of patients with autoimmune hepatitis and antibodies to liver-kidney microsomal (LKM) antigen (anti-LKM) (Chap. 362). Immune complex–mediated tissue damage appears to play a pathogenetic role in the extrahepatic manifestations of acute hepatitis B. The occasional prodromal serum sickness–like syndrome observed in acute hepatitis B appears to be related to the deposition in tissue blood vessel walls of HBsAg-anti-HBs circulating immune complexes, leading to activation of the complement system and depressed serum complement levels.


InternalMed_Harrison

InternalMed_Harrison. In patients with chronic hepatitis B, other types of immune-complex disease may be seen. Glomerulonephritis with the nephrotic syndrome is observed occasionally; HBsAg, immunoglobulin, and C3 deposition has been found in the glomerular basement membrane. Whereas generalized vasculitis (polyarteritis nodosa) develops in considerably fewer than 1% of patients with chronic HBV infection, 20–30% of patients with polyarteritis nodosa have HBsAg in serum (Chap. 385). In these patients, the affected smalland medium-size arterioles contain 2012 HBsAg, immunoglobulins, and complement components. Another extrahepatic manifestation of viral hepatitis, essential mixed cryoglobulinemia (EMC), was reported initially to be associated with hepatitis


InternalMed_Harrison

InternalMed_Harrison. B. The disorder is characterized clinically by arthritis, cutaneous vasculitis (palpable purpura), and occasionally, glomerulonephritis and serologically by the presence of circulating cryoprecipitable immune complexes of more than one immunoglobulin class (Chaps. 338 and 385). Many patients with this syndrome have chronic liver disease, but the association with HBV infection is limited; instead, a substantial proportion has chronic HCV infection, with circulating immune complexes containing HCV RNA. Immune-complex glomerulonephritis is another recognized extrahepatic manifestation of chronic hepatitis C.


InternalMed_Harrison

InternalMed_Harrison. The typical morphologic lesions of all types of viral hepatitis are similar and consist of panlobular infiltration with mononuclear cells, hepatic cell necrosis, hyperplasia of Kupffer cells, and variable degrees of cholestasis. Hepatic cell regeneration is present, as evidenced by numerous mitotic figures, multinucleated cells, and “rosette” or “pseudoacinar” formation. The mononuclear infiltration consists primarily of small lymphocytes, although plasma cells and eosinophils occasionally are present. Liver cell damage consists of hepatic cell degeneration and necrosis, cell dropout, ballooning of cells, and acidophilic degeneration of hepatocytes (forming so-called Councilman or apoptotic bodies). Large hepatocytes with a ground-glass appearance of the cytoplasm may be seen in chronic but not in acute HBV infection; these cells contain HBsAg and can be identified histochemically with orcein or aldehyde fuchsin. In uncomplicated viral hepatitis, the reticulin framework is preserved.


InternalMed_Harrison

InternalMed_Harrison. In hepatitis C, the histologic lesion is often remarkable for a relative paucity of inflammation, a marked increase in activation of sinusoidal lining cells, lymphoid aggregates, the presence of fat (more frequent in genotype 3 and linked to increased fibrosis), and, occasionally, bile duct lesions in which biliary epithelial cells appear to be piled up without interruption of the basement membrane. Occasionally, microvesicular steatosis occurs in hepatitis D. In hepatitis E, a common histologic feature is marked cholestasis. A cholestatic variant of slowly resolving acute hepatitis A also has been described.


InternalMed_Harrison

InternalMed_Harrison. A more severe histologic lesion, bridging hepatic necrosis, also termed subacute or confluent necrosis or interface hepatitis, is observed occasionally in acute hepatitis. “Bridging” between lobules results from large areas of hepatic cell dropout, with collapse of the reticulin framework. Characteristically, the bridge consists of condensed reticulum, inflammatory debris, and degenerating liver cells that span adjacent portal areas, portal to central veins, or central vein to central vein. This lesion had been thought to have prognostic significance; in many of the originally described patients with this lesion, a subacute course terminated in death within several weeks to months, or severe chronic hepatitis and cirrhosis developed; however, the association between bridging necrosis and a poor prognosis in patients with acute hepatitis has not been upheld. Therefore, although demonstration of this lesion in patients with chronic hepatitis has prognostic significance (Chap. 362), its


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InternalMed_Harrison. a poor prognosis in patients with acute hepatitis has not been upheld. Therefore, although demonstration of this lesion in patients with chronic hepatitis has prognostic significance (Chap. 362), its demonstration during acute hepatitis is less meaningful, and liver biopsies to identify this lesion are no longer undertaken routinely in patients with acute hepatitis. In massive hepatic necrosis (fulminant hepatitis, “acute yellow atrophy”), the striking feature at postmortem examination is the finding of a small, shrunken, soft liver. Histologic examination reveals massive necrosis and dropout of liver cells of most lobules with extensive collapse and condensation of the reticulin framework. When histologic documentation is required in the management of fulminant or very severe hepatitis, a biopsy can be done by the angiographically guided transjugular route, which permits the performance of this invasive procedure in the presence of severe coagulopathy.


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InternalMed_Harrison. Immunohistochemical and electron-microscopic studies have localized HBsAg to the cytoplasm and plasma membrane of infected liver cells. In contrast, HBcAg predominates in the nucleus, but, occasionally, scant amounts are also seen in the cytoplasm and on the cell membrane. HDV antigen is localized to the hepatocyte nucleus, whereas HAV, HCV, and HEV antigens are localized to the cytoplasm. Before the availability of serologic tests for hepatitis viruses, all viral hepatitis cases were labeled either as “infectious” or “serum” hepatitis. Modes of transmission overlap, however, and a clear distinction among the different types of viral hepatitis cannot be made solely on the basis of clinical or epidemiologic features (Table 360-2). The most accurate means to distinguish the various types of viral hepatitis involves specific serologic testing.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis A This agent is transmitted almost exclusively by the fecal-oral route. Person-to-person spread of HAV is enhanced by poor personal hygiene and overcrowding; large outbreaks as well as sporadic cases have been traced to contaminated food, water, milk, frozen raspberries and strawberries, green onions imported from Mexico, and shellfish. Intrafamily and intrainstitutional spread are also common. Early epidemiologic observations supported a predilection for hepatitis A to occur in late fall and early winter. In temperate zones, epidemic waves have been recorded every 5–20 years as new segments of nonimmune population appeared; however, in developed countries, the incidence of hepatitis A has been declining, presumably as a function of improved sanitation, and these cyclic patterns are no longer observed. No HAV carrier state has been identified after acute hepatitis A; perpetuation of the virus in nature depends presumably on nonepidemic, inapparent subclinical infection,


InternalMed_Harrison

InternalMed_Harrison. are no longer observed. No HAV carrier state has been identified after acute hepatitis A; perpetuation of the virus in nature depends presumably on nonepidemic, inapparent subclinical infection, ingestion of contaminated food or water in, or imported from, endemic areas, and/or contamination linked to environmental reservoirs.


InternalMed_Harrison

InternalMed_Harrison. In the general population, anti-HAV, a marker for previous HAV infection, increases in prevalence as a function of increasing age and of decreasing socioeconomic status. In the 1970s, serologic evidence of prior hepatitis A infection occurred in ~40% of urban populations in the United States, most of whose members never recalled having had a symptomatic case of hepatitis. In subsequent decades, however, the prevalence of anti-HAV has been declining in the United States. In developing countries, exposure, infection, and subsequent immunity are almost universal in childhood. As the frequency of subclinical childhood infections declines in developed countries, a susceptible cohort of adults emerges. Hepatitis A tends to be more symptomatic in adults; therefore, paradoxically, as the frequency of HAV infection declines, the likelihood of clinically apparent, even severe, HAV illnesses increases in the susceptible adult population. Travel to endemic areas is a common source of infection


InternalMed_Harrison

InternalMed_Harrison. of HAV infection declines, the likelihood of clinically apparent, even severe, HAV illnesses increases in the susceptible adult population. Travel to endemic areas is a common source of infection for adults from nonendemic areas. More recently recognized epidemiologic foci of HAV infection include child care centers, neonatal intensive care units, promiscuous men who have sex with men, injection drug users, and unvaccinated close contacts of newly arrived international adopted children, most of whom emanate from countries with intermediate-to-high hepatitis A endemicity. Although hepatitis A is rarely bloodborne, several outbreaks have been recognized in recipients of clotting-factor concentrates. In the United States, the introduction of hepatitis A vaccination programs among children from high-incidence states has resulted in a >70% reduction in the annual incidence of new HAV infections and has shifted the burden of new infections from children to young adults. In the most recent,


InternalMed_Harrison

InternalMed_Harrison. high-incidence states has resulted in a >70% reduction in the annual incidence of new HAV infections and has shifted the burden of new infections from children to young adults. In the most recent, 1999–2006 U.S. Public Health Service National Health and Nutrition Examination Survey (NHANES), the prevalence of anti-HAV in the U.S. population was 35%, representing (compared to the 1988–1994 survey) a stable frequency of infection and natural immunity in adults >19 years old but an increase in vaccine-induced immunity for children age 6–19 years.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis B Percutaneous inoculation has long been recognized as a major route of hepatitis B transmission, but the outmoded designation “serum hepatitis” is an inaccurate label for the epidemiologic spectrum of HBV infection. As detailed below, most of the hepatitis transmitted by blood transfusion is not caused by HBV; moreover, in approximately two-thirds of patients with acute type B hepatitis, no history of an identifiable percutaneous exposure can be elicited. We now recognize that many cases of hepatitis B result from less obvious modes of nonpercutaneous or covert percutaneous transmission. HBsAg has been identified in almost every body fluid from aPrimarily with HIV co-infection and high-level viremia in index case; risk ~5%. bUp to 5% in acute HBV/HDV co-infection; up to 20% in HDV superinfection of chronic HBV infection. c Varies considerably throughout the world and in subpopulations within countries; see text. dIn acute HBV/HDV co-infection, the frequency of chronicity is


InternalMed_Harrison

InternalMed_Harrison. superinfection of chronic HBV infection. c Varies considerably throughout the world and in subpopulations within countries; see text. dIn acute HBV/HDV co-infection, the frequency of chronicity is the same as that for HBV; in HDV superinfection, chronicity is invariable. e10–20% in pregnant women. f Except as observed in immunosuppressed liver allograft recipients or other immunosuppressed hosts. gCommon in Mediterranean countries; rare in North America and western Europe. hAnecdotal reports and retrospective studies suggest that pegylated interferon and/or ribavirin are effective in treating chronic hepatitis E, observed in immunocompromised persons.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: HBIG, hepatitis B immunoglobulin. See text for other abbreviations. infected persons, and at least some of these body fluids—most notably semen and saliva—are infectious, albeit less so than serum, when administered percutaneously or nonpercutaneously to experimental animals. Among the nonpercutaneous modes of HBV transmission, oral ingestion has been documented as a potential but inefficient route of exposure. By contrast, the two nonpercutaneous routes considered to have the greatest impact are intimate (especially sexual) contact and perinatal transmission.


InternalMed_Harrison

InternalMed_Harrison. In sub-Saharan Africa, intimate contact among toddlers is considered instrumental in contributing to the maintenance of the high frequency of hepatitis B in the population. Perinatal transmission occurs primarily in infants born to mothers with chronic hepatitis B or (rarely) mothers with acute hepatitis B during the third trimester of pregnancy or during the early postpartum period. Perinatal transmission is uncommon in North America and western Europe but occurs with great frequency and is the most important mode of HBV perpetuation in East Asia and developing countries. Although the precise mode of perinatal transmission is unknown, and although ~10% of infections may be acquired in utero, epidemiologic evidence suggests that most infections occur approximately at the time of delivery and are not related to breast-feeding. The likelihood of perinatal transmission of HBV correlates with the presence of HBeAg and high-level viral replication; 90% of HBeAg-positive mothers but only


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InternalMed_Harrison. and are not related to breast-feeding. The likelihood of perinatal transmission of HBV correlates with the presence of HBeAg and high-level viral replication; 90% of HBeAg-positive mothers but only 10–15% of anti-HBe-positive mothers transmit HBV infection to their offspring. In most cases, acute infection in the neonate is clinically asymptomatic, but the child is very likely to remain chronically infected.


InternalMed_Harrison

InternalMed_Harrison. The >350–400 million HBsAg carriers in the world constitute the main reservoir of hepatitis B in human beings. Whereas serum HBsAg is infrequent (0.1–0.5%) in normal populations in the United States and western Europe, a prevalence of up to 5–20% has been found in East Asia and in some tropical countries; in persons with Down’s syndrome, lepromatous leprosy, leukemia, Hodgkin’s disease, or polyarteritis nodosa; in patients with chronic renal disease on hemodialysis; and in injection drug users.


InternalMed_Harrison

InternalMed_Harrison. Other groups with high rates of HBV infection include spouses of acutely infected persons; sexually promiscuous persons (especially promiscuous men who have sex with men); health care workers exposed to blood; persons who require repeated transfusions especially with pooled blood-product concentrates (e.g., hemophiliacs); residents and staff of custodial institutions for the developmentally handicapped; prisoners; and, to a lesser extent, family members of chronically infected patients. In volunteer blood donors, the prevalence of anti-HBs, a reflection of previous HBV infection, ranges from 5–10%, but the prevalence is higher in lower socioeconomic strata, older age groups, and per-sons—including those mentioned above—exposed to blood products. Because of highly sensitive virologic screening of donor blood, the risk of acquiring HBV infection from a blood transfusion is 1 in 230,000.


InternalMed_Harrison

InternalMed_Harrison. Prevalence of infection, modes of transmission, and human behavior conspire to mold geographically different epidemiologic patterns of HBV infection. In East Asia and Africa, hepatitis B, a disease of the newborn and young children, is perpetuated by a cycle of maternal-neonatal spread. In North America and western Europe, hepatitis B is primarily a disease of adolescence and early adulthood, the time of life when intimate sexual contact and recreational and occupational percutaneous exposures tend to occur. To some degree, however, this dichotomy between high-prevalence and low-prevalence geographic regions has been minimized by immigration from high-prevalence to low-prevalence areas. The introduction of hepatitis B vaccine in the early 1980s and adoption of universal childhood vaccination policies in many countries resulted in a dramatic, ~90% decline in the incidence of new HBV infections in those countries as well as in the dire


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InternalMed_Harrison. Persons born in countries/regions with a high (≥8%) and intermediate (≥2%) prevalence of HBV infection including immigrants and adopted children and including persons born in the United States who were not vaccinated as infants and whose parents emigrated from areas of high HBV endemicity Household and sexual contacts of persons with hepatitis B Babies born to HBsAg-positive mothers Persons with multiple sexual contacts or a history of sexually transmitted disease Men who have sex with men Inmates of correctional facilities Persons with elevated alanine or aspartate aminotransferase levels Persons with HCV or HIV infection Persons who are the source of blood or body fluids that would be an indication for postexposure prophylaxis (e.g., needlestick, mucosal exposure, sexual assault) consequences of chronic infection, including hepatocellular carcinoma. Populations and groups for whom HBV infection screening is recommended are listed in Table 360-3.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis D Infection with HDV has a worldwide distribution, but two epidemiologic patterns exist. In Mediterranean countries (northern Africa, southern Europe, the Middle East), HDV infection is endemic among those with hepatitis B, and the disease is transmitted predominantly by nonpercutaneous means, especially close personal contact. In nonendemic areas, such as the United States and northern Europe, HDV infection is confined to persons exposed frequently to blood and blood products, primarily injection drug users and hemophiliacs. HDV infection can be introduced into a population through drug users or by migration of persons from endemic to nonendemic areas. Thus, patterns of population migration and human behavior facilitating percutaneous contact play important roles in the introduction and amplification of HDV infection. Occasionally, the migrating epidemiology of hepatitis D is expressed in explosive outbreaks of severe hepatitis, such as those that have occurred in remote


InternalMed_Harrison

InternalMed_Harrison. and amplification of HDV infection. Occasionally, the migrating epidemiology of hepatitis D is expressed in explosive outbreaks of severe hepatitis, such as those that have occurred in remote South American villages as well as in urban centers in the United States. Ultimately, such outbreaks of hepatitis D—either of co-infections with acute hepatitis B or of superinfections in those already infected with HBV—may blur the distinctions between endemic and nonendemic areas. On a global scale, HDV infection declined at the end of the 1990s. Even in Italy, an HDV-endemic area, public health measures introduced to control HBV infection resulted during the 1990s in a 1.5%/year reduction in the prevalence of HDV infection. Still, the frequency of HDV infection during the first decade of the twenty-first century has not fallen below levels reached during the 1990s; the reservoir has been sustained by survivors infected during 1970–1980 and recent immigrants from still-endemic to less-endemic


InternalMed_Harrison

InternalMed_Harrison. century has not fallen below levels reached during the 1990s; the reservoir has been sustained by survivors infected during 1970–1980 and recent immigrants from still-endemic to less-endemic countries.


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InternalMed_Harrison. Hepatitis C Routine screening of blood donors for HBsAg and the elimination of commercial blood sources in the early 1970s reduced the frequency of, but did not eliminate, transfusion-associated hepatitis. During the 1970s, the likelihood of acquiring hepatitis after transfusion of voluntarily donated, HBsAg-screened blood was ~10% per patient (up to 0.9% per unit transfused); 90–95% of these cases were classified, based on serologic exclusion of hepatitis A and B, as “non-A, non-B” hepatitis. For patients requiring transfusion of pooled products, such as clotting factor concentrates, the risk was even higher, up to 20–30%.


InternalMed_Harrison

InternalMed_Harrison. During the 1980s, voluntary self-exclusion of blood donors with risk factors for AIDS and then the introduction of donor screening for anti-HIV reduced further the likelihood of transfusion-associated hepatitis to <5%. During the late 1980s and early 1990s, the introduction first of “surrogate” screening tests for non-A, non-B hepatitis (alanine aminotransferase [ALT] and anti-HBc, both shown to identify blood donors with a higher likelihood of transmitting non-A, non-B hepatitis to recipients) and, subsequently, after the discovery of HCV, first-generation immunoassays for anti-HCV reduced the frequency of transfusion-associated hepatitis even further. A prospective analysis of transfusion-associated hepatitis conducted between 1986 and 1990 showed that the frequency of transfusion-associated hepatitis at one urban university hospital fell from a baseline of 3.8% per patient (0.45% per unit transfused) to 1.5% per patient (0.19% per unit) after the introduction of surrogate testing


InternalMed_Harrison

InternalMed_Harrison. hepatitis at one urban university hospital fell from a baseline of 3.8% per patient (0.45% per unit transfused) to 1.5% per patient (0.19% per unit) after the introduction of surrogate testing and to 0.6% per patient (0.03% per unit) after the introduction of first-generation anti-HCV assays. The introduction of second-generation anti-HCV assays reduced the frequency of transfusion-associated hepatitis C to almost imperceptible levels—1 in 100,000—and these gains were reinforced by the application of third-generation anti-HCV assays and of automated PCR testing of donated blood for HCV RNA, which has resulted in a reduction in the risk of transfusion-associated HCV infection to 1 in 2.3 million transfusions.


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InternalMed_Harrison. In addition to being transmitted by transfusion, hepatitis C can be transmitted by other percutaneous routes, such as injection drug use. In addition, this virus can be transmitted by occupational exposure to blood, and the likelihood of infection is increased in hemodialysis units. Although the frequency of transfusion-associated hepatitis C fell as a result of blood-donor screening, the overall frequency of hepatitis C remained the same until the early 1990s, when the overall frequency fell by 80%, in parallel with a reduction in the number of new cases in injection drug users. After the exclusion of anti-HCV-positive plasma units from the donor pool, rare, sporadic instances have occurred of hepatitis C among recipients of immunoglobulin (Ig) preparations for intravenous (but not intramuscular) use.


InternalMed_Harrison

InternalMed_Harrison. Serologic evidence for HCV infection occurs in 90% of patients with a history of transfusion-associated hepatitis (almost all occurring before 1992, when second-generation HCV screening tests were introduced); hemophiliacs and others treated with clotting factors; injection drug users; 60–70% of patients with sporadic “non-A, non-B” hepatitis who lack identifiable risk factors; 0.5% of volunteer blood donors; and, in a survey conducted in the United States between 1999 and 2002, 1.6% of the general population in the United States, which translates into 4.1 million persons (3.2 million with viremia), the majority of whom are unaware of their infections. Moreover, such population surveys do not include higher-risk groups such as incarcerated prisoners and active injection drug users, indicating that the actual prevalence is even higher. Comparable frequencies of HCV infection occur in most countries around the world, with 170 million persons infected worldwide, but extraordinarily high


InternalMed_Harrison

InternalMed_Harrison. that the actual prevalence is even higher. Comparable frequencies of HCV infection occur in most countries around the world, with 170 million persons infected worldwide, but extraordinarily high prevalences of HCV infection occur in certain countries such as Egypt, where >20% of the population (as high as 50% in persons born prior to 1960) in some cities is infected. The high frequency in Egypt is attributable to contaminated equipment used for medical procedures and unsafe injection practices in the 1950s to 1980s (during a campaign to eradicate schistosomiasis with intravenous tartar emetic). In the United States, African Americans and Mexican Americans have higher frequencies of HCV infection than whites. Between 1988 and 1994, 30to 40-year-old adult males had the highest prevalence of HCV infection; however, in a survey conducted between 1999 and 2002, the peak age decile had shifted to those age 40–49 years; an increase in hepatitis C–related mortality has paralleled this secular


InternalMed_Harrison

InternalMed_Harrison. HCV infection; however, in a survey conducted between 1999 and 2002, the peak age decile had shifted to those age 40–49 years; an increase in hepatitis C–related mortality has paralleled this secular trend, increasing since 1995 predominantly in the 45to 65-year age group. Thus, despite an 80% reduction in new HCV infections during the 1990s, the prevalence of HCV infection in the population was sustained by an aging cohort that had acquired their infections three to four decades earlier, during the 1960s and 1970s, as a result predominantly of self-inoculation with recreational drugs. As death resulting from HIV infection fell after 1999, age-adjusted mortality associated with HCV infection surpassed that of HIV infection in 2007; >70% of HCV-associated deaths occurred in the “baby boomer” cohort born between 1945 and 1965. Compared to the 1.6% prevalence of HCV infection in the population at large, the prevalence in the 1945–1965 birth cohort was 3.2%, representing three-quarters of


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InternalMed_Harrison. cohort born between 1945 and 1965. Compared to the 1.6% prevalence of HCV infection in the population at large, the prevalence in the 1945–1965 birth cohort was 3.2%, representing three-quarters of all infected persons. Therefore, in 2012, the Centers for Disease Control and Prevention recommended that all persons born between 1945 and 1965 be screened for hepatitis C, without ascertainment of risk, a recommendation shown to be cost-effective and predicted to identify 800,000 infected persons. Because of the availability of highly effective antiviral therapy, such screening would have the potential to avert 200,000 cases of cirrhosis and 47,000 cases of hepatocellular carcinoma and to prevent 120,000 hepatitis-related deaths.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis C accounts for 40% of chronic liver disease, is the most frequent indication for liver transplantation, and is estimated to account for 8000–10,000 deaths per year in the United States. The distribution of HCV genotypes varies in different parts of the world. Worldwide, genotype 1 is the most common. In the United States, genotype 1 accounts for 70% of HCV infections, whereas genotypes 2 and 3 account for the remaining 30%; among African Americans, the frequency of genotype 1 is even higher (i.e., 90%). Genotype 4 predominates in Egypt; genotype 5 is localized to South Africa, genotype 6 to Hong Kong, and genotype 7 to Central Africa. Most asymptomatic blood donors found to have anti-HCV and ~20–30% of persons with reported cases of acute hepatitis C do not fall into a recognized risk group; however, many such blood donors do recall risk-associated behaviors when questioned carefully.


InternalMed_Harrison

InternalMed_Harrison. As a bloodborne infection, HCV potentially can be transmitted sexually and perinatally; however, both of these modes of transmission are inefficient for hepatitis C. Although 10–15% of patients with acute hepatitis C report having potential sexual sources of infection, most studies have failed to identify sexual transmission of this agent. The chances of sexual and perinatal transmission have been estimated to be ~5% but shown in a prospective study to be only 1% between monogamous sexual partners, well below comparable rates for HIV and HBV infections. Moreover, sexual transmission appears to be confined to such subgroups as persons with multiple sexual partners and sexually transmitted diseases. Breast-feeding does not increase the risk of HCV infection between an infected mother and her infant. Infection of health workers is not dramatically higher than among the general population; however, health workers are more likely to acquire HCV infection through accidental needle


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InternalMed_Harrison. and her infant. Infection of health workers is not dramatically higher than among the general population; however, health workers are more likely to acquire HCV infection through accidental needle punctures, the efficiency of which is ~3%. Infection of household contacts is rare as well.


InternalMed_Harrison

InternalMed_Harrison. Besides persons born between 1945 and 1965, other groups with an increased frequency of HCV infection are listed in Table 360-4. In immunosuppressed individuals, levels of anti-HCV may be undetectable, and a diagnosis may require testing for HCV RNA. Although new acute cases of hepatitis C are rare, newly diagnosed cases are common among otherwise healthy persons who experimented briefly with injection drugs, as noted above, three or four decades earlier. Such instances usually remain unrecognized for years, until unearthed by laboratory screening for routine medical examinations, insurance applications, and attempted blood donation. Although, overall, the annual incidence of new HCV infections has continued to fall, the rate of new infections has been increasing since 2002 in a new cohort


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InternalMed_Harrison. Persons born between 1945 and 1965 Persons who have ever used injection drugs Persons with HIV infection Hemophiliacs treated with clotting factor concentrates prior to 1987 Persons who have ever undergone long-term hemodialysis Persons with unexplained elevations of aminotransferase levels Transfusion or transplantation recipients prior to July 1992 Recipients of blood or organs from a donor found to be positive for hepatitis C Children born to women with hepatitis C Health care, public safety, and emergency medical personnel following needle injury or mucosal exposure to HCV-contaminated blood Sexual partners of persons with hepatitis C infection of young injection drug users, age 15–24 years (accounting for more 2015 than two-thirds of all acute cases), who, unlike older cohorts, had not learned to take precautions to prevent bloodborne infections.


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InternalMed_Harrison. Hepatitis E This type of hepatitis, identified in India, Asia, Africa, the Middle East, and Central America, resembles hepatitis A in its primarily enteric mode of spread. The commonly recognized cases occur after contamination of water supplies such as after monsoon flooding, but sporadic, isolated cases occur. An epidemiologic feature that distinguishes HEV from other enteric agents is the rarity of secondary person-to-person spread from infected persons to their close contacts. Large waterborne outbreaks in endemic areas are linked to genotypes 1 and 2, arise in populations that are immune to HAV, favor young adults, and account for antibody prevalences of 30–80%. In nonendemic areas of the world, such as the United States, clinically apparent acute hepatitis E is extremely rare; however, during the 1988–1994 NHANES survey conducted by the U.S. Public Health Service, the prevalence of anti-HEV was 21%, reflecting subclinical infections, infection with genotypes 3 and 4,


InternalMed_Harrison

InternalMed_Harrison. rare; however, during the 1988–1994 NHANES survey conducted by the U.S. Public Health Service, the prevalence of anti-HEV was 21%, reflecting subclinical infections, infection with genotypes 3 and 4, predominantly in older males (>60 years). In nonendemic areas, HEV accounts hardly at all for cases of sporadic hepatitis; however, cases imported from endemic areas have been found in the United States. Evidence supports a zoonotic reservoir for HEV primarily in swine, which may account for the mostly subclinical infections in nonendemic areas.


InternalMed_Harrison

InternalMed_Harrison. CLINICAL AND LABORATORY FEATURES Symptoms and Signs Acute viral hepatitis occurs after an incubation period that varies according to the responsible agent. Generally, incubation periods for hepatitis A range from 15–45 days (mean, 4 weeks), for hepatitis B and D from 30–180 days (mean, 8–12 weeks), for hepatitis C from 15–160 days (mean, 7 weeks), and for hepatitis E from 14–60 days (mean, 5–6 weeks). The prodromal symptoms of acute viral hepatitis are systemic and quite variable. Constitutional symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza may precede the onset of jaundice by 1–2 weeks. The nausea, vomiting, and anorexia are frequently associated with alterations in olfaction and taste. A low-grade fever between 38° and 39°C (100°–102°F) is more often present in hepatitis A and E than in hepatitis B or C, except when hepatitis B is heralded by a serum sickness–like syndrome; rarely, a fever of


InternalMed_Harrison

InternalMed_Harrison. fever between 38° and 39°C (100°–102°F) is more often present in hepatitis A and E than in hepatitis B or C, except when hepatitis B is heralded by a serum sickness–like syndrome; rarely, a fever of 39.5°–40°C (103°–104°F) may accompany the constitutional symptoms. Dark urine and clay-colored stools may be noticed by the patient from 1–5 days before the onset of clinical jaundice.


InternalMed_Harrison

InternalMed_Harrison. With the onset of clinical jaundice, the constitutional prodromal symptoms usually diminish, but in some patients, mild weight loss (2.5–5 kg) is common and may continue during the entire icteric phase. The liver becomes enlarged and tender and may be associated with right upper quadrant pain and discomfort. Infrequently, patients present with a cholestatic picture, suggesting extrahepatic biliary obstruction. Splenomegaly and cervical adenopathy are present in 10–20% of patients with acute hepatitis. Rarely, a few spider angiomas appear during the icteric phase and disappear during convalescence. During the recovery phase, constitutional symptoms disappear, but usually some liver enlargement and abnormalities in liver biochemical tests are still evident. The duration of the posticteric phase is variable, ranging from 2–12 weeks, and is usually more prolonged in acute hepatitis B and C. Complete clinical and biochemical recovery is to be expected 1–2 months after all cases of


InternalMed_Harrison

InternalMed_Harrison. phase is variable, ranging from 2–12 weeks, and is usually more prolonged in acute hepatitis B and C. Complete clinical and biochemical recovery is to be expected 1–2 months after all cases of hepatitis A and E and 3–4 months after the onset of jaundice in three-quarters of uncomplicated, self-limited cases of hepatitis B and C (among healthy adults, acute hepatitis B is self-limited in 95–99%, whereas hepatitis C is self-limited in only ~15%). In the remainder, biochemical recovery may be delayed. A substantial proportion of patients with viral hepatitis never become icteric.


InternalMed_Harrison

InternalMed_Harrison. Infection with HDV can occur in the presence of acute or chronic HBV infection; the duration of HBV infection determines the duration of HDV infection. When acute HDV and HBV infection occur simultaneously, clinical and biochemical features may be indistinguishable from those of HBV infection alone, although occasionally they are 2016 more severe. As opposed to patients with acute HBV infection, patients with chronic HBV infection can support HDV replication indefinitely, as when acute HDV infection occurs in the presence of a nonresolving acute HBV infection or, more commonly, when acute hepatitis D is superimposed on underlying chronic hepatitis B. In such cases, the HDV superinfection appears as a clinical exacerbation or an episode resembling acute viral hepatitis in someone already chronically infected with HBV. Superinfection with HDV in a patient with chronic hepatitis B often leads to clinical deterioration (see below). In addition to superinfections with other hepatitis


InternalMed_Harrison

InternalMed_Harrison. chronically infected with HBV. Superinfection with HDV in a patient with chronic hepatitis B often leads to clinical deterioration (see below). In addition to superinfections with other hepatitis agents, acute hepatitis-like clinical events in persons with chronic hepatitis B may accompany spontaneous HBeAg to anti-HBe seroconversion or spontaneous reactivation (i.e., reversion from relatively nonreplicative to replicative infection). Such reactivations can occur as well in therapeutically immunosuppressed patients with chronic HBV infection when cytotoxic/immunosuppressive drugs are withdrawn; in these cases, restoration of immune competence is thought to allow resumption of previously checked cell-mediated immune cytolysis of HBV-infected hepatocytes. Occasionally, acute clinical exacerbations of chronic hepatitis B may represent the emergence of a precore mutant (see “Virology and Etiology”), and the subsequent course in such patients may be characterized by periodic exacerbations.


InternalMed_Harrison

InternalMed_Harrison. of chronic hepatitis B may represent the emergence of a precore mutant (see “Virology and Etiology”), and the subsequent course in such patients may be characterized by periodic exacerbations. Cytotoxic chemotherapy can lead to reactivation of chronic hepatitis C as well, and anti-TNF-α therapy can lead to reactivation of both hepatitis B and C.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Features The serum aminotransferases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (previously designated SGOT and SGPT) increase to a variable degree during the prodromal phase of acute viral hepatitis and precede the rise in bilirubin level (Figs. 360-2 and 360-4). The level of these enzymes, however, does not correlate well with the degree of liver cell damage. Peak levels vary from 400–4000 IU or more; these levels are usually reached at the time the patient is clinically icteric and diminish progressively during the recovery phase of acute hepatitis. The diagnosis of anicteric hepatitis is based on clinical features and on aminotransferase elevations.


InternalMed_Harrison

InternalMed_Harrison. Jaundice is usually visible in the sclera or skin when the serum bilirubin value is >43 μmol/L (2.5 mg/dL). When jaundice appears, the serum bilirubin typically rises to levels ranging from 85–340 μmol/L (5–20 mg/dL). The serum bilirubin may continue to rise despite falling serum aminotransferase levels. In most instances, the total bilirubin is equally divided between the conjugated and unconjugated fractions. Bilirubin levels >340 μmol/L (20 mg/dL) extending and persisting late into the course of viral hepatitis are more likely to be associated with severe disease. In certain patients with underlying hemolytic anemia, however, such as glucose-6-phosphate dehydrogenase deficiency and sickle cell anemia, a high serum bilirubin level is common, resulting from superimposed hemolysis. In such patients, bilirubin levels >513 μmol/L (30 mg/dL) have been observed and are not necessarily associated with a poor prognosis.


InternalMed_Harrison

InternalMed_Harrison. Neutropenia and lymphopenia are transient and are followed by a relative lymphocytosis. Atypical lymphocytes (varying between 2 and 20%) are common during the acute phase. Measurement of the prothrombin time (PT) is important in patients with acute viral hepatitis, because a prolonged value may reflect a severe hepatic synthetic defect, signify extensive hepatocellular necrosis, and indicate a worse prognosis. Occasionally, a prolonged PT may occur with only mild increases in the serum bilirubin and aminotransferase levels. Prolonged nausea and vomiting, inadequate carbohydrate intake, and poor hepatic glycogen reserves may contribute to hypoglycemia noted occasionally in patients with severe viral hepatitis. Serum alkaline phosphatase may be normal or only mildly elevated, whereas a fall in serum albumin is uncommon in uncomplicated acute viral hepatitis. In some patients, mild and transient steatorrhea has been noted, as well as slight microscopic hematuria and minimal proteinuria.


InternalMed_Harrison

InternalMed_Harrison. A diffuse but mild elevation of the γ globulin fraction is common during acute viral hepatitis. Serum IgG and IgM levels are elevated in about one-third of patients during the acute phase of viral hepatitis, but the serum IgM level is elevated more characteristically during acute hepatitis A. During the acute phase of viral hepatitis, antibodies to smooth muscle and other cell constituents may be present, and low titers of rheumatoid factor, nuclear antibody, and heterophile antibody can also be found occasionally. In hepatitis C and D, antibodies to LKM may occur; however, the species of LKM antibodies in the two types of hepatitis are different from each other as well as from the LKM antibody species characteristic of autoimmune hepatitis type 2 (Chap. 362). The autoantibodies in viral hepatitis are nonspecific and can also be associated with other viral and systemic diseases. In contrast, virus-specific antibodies, which appear during and after hepatitis virus infection, are


InternalMed_Harrison

InternalMed_Harrison. viral hepatitis are nonspecific and can also be associated with other viral and systemic diseases. In contrast, virus-specific antibodies, which appear during and after hepatitis virus infection, are serologic markers of diagnostic importance.


InternalMed_Harrison

InternalMed_Harrison. As described above, serologic tests are available routinely with which to establish a diagnosis of hepatitis A, B, D, and C. Tests for fecal or serum HAV are not routinely available. Therefore, a diagnosis of hepatitis A is based on detection of IgM anti-HAV during acute illness (Fig. 360-2). Rheumatoid factor can give rise to false-positive results in this test. A diagnosis of HBV infection can usually be made by detection of HBsAg in serum. Infrequently, levels of HBsAg are too low to be detected during acute HBV infection, even with contemporary, highly sensitive immunoassays. In such cases, the diagnosis can be established by the presence of IgM anti-HBc.


InternalMed_Harrison

InternalMed_Harrison. The titer of HBsAg bears little relation to the severity of clinical disease. Indeed, an inverse correlation exists between the serum concentration of HBsAg and the degree of liver cell damage. For example, titers are highest in immunosuppressed patients, lower in patients with chronic liver disease (but higher in mild chronic than in severe chronic hepatitis), and very low in patients with acute fulminant hepatitis. These observations suggest that, in hepatitis B, the degree of liver cell damage and the clinical course are related to variations in the patient’s immune response to HBV rather than to the amount of circulating HBsAg. In immunocompetent persons, however, a correlation exists between markers of HBV replication and liver injury (see below).


InternalMed_Harrison

InternalMed_Harrison. Another important serologic marker in patients with hepatitis B is HBeAg. Its principal clinical usefulness is as an indicator of relative infectivity. Because HBeAg is invariably present during early acute hepatitis B, HBeAg testing is indicated primarily in chronic infection. In patients with hepatitis B surface antigenemia of unknown duration (e.g., blood donors found to be HBsAg-positive) testing for IgM anti-HBc may be useful to distinguish between acute or recent infection (IgM anti-HBc-positive) and chronic HBV infection (IgM antiHBc-negative, IgG anti-HBc-positive). A false-positive test for IgM anti-HBc may be encountered in patients with high-titer rheumatoid factor. Also, IgM anti-HBc may be reexpressed during acute reactivation of chronic hepatitis B.


InternalMed_Harrison

InternalMed_Harrison. Anti-HBs is rarely detectable in the presence of HBsAg in patients with acute hepatitis B, but 10–20% of persons with chronic HBV infection may harbor low-level anti-HBs. This antibody is directed not against the common group determinant, a, but against the heterotypic subtype determinant (e.g., HBsAg of subtype ad with anti-HBs of subtype y). In most cases, this serologic pattern cannot be attributed to infection with two different HBV subtypes, and the presence of this antibody is not a harbinger of imminent HBsAg clearance. When such antibody is detected, its presence is of no recognized clinical significance (see “Virology and Etiology”).


InternalMed_Harrison

InternalMed_Harrison. After immunization with hepatitis B vaccine, which consists of HBsAg alone, anti-HBs is the only serologic marker to appear. The commonly encountered serologic patterns of hepatitis B and their interpretations are summarized in Table 360-5. Tests for the detection of HBV DNA in liver and serum are now available. Like HBeAg, serum HBV DNA is an indicator of HBV replication, but tests for HBV DNA are more sensitive and quantitative. First-generation hybridization assays for HBV DNA had a sensitivity of 105−106 virions/mL, a relative threshold below which infectivity and liver injury are limited and HBeAg is usually undetectable. Currently, testing for HBV DNA has shifted from insensitive hybridization assays to amplification assays (e.g., the PCR-based assay, which can detect as few as 10 or 100 virions/mL); among the commercially available PCR assays, the most useful are those with the highest sensitivity (5–10 IU/mL) and the largest dynamic range (100–109 IU/mL). With increased


InternalMed_Harrison

InternalMed_Harrison. 10 or 100 virions/mL); among the commercially available PCR assays, the most useful are those with the highest sensitivity (5–10 IU/mL) and the largest dynamic range (100–109 IU/mL). With increased sensitivity, fied. The other involves target ampli + − IgM + − Acute hepatitis B, high infectivitya fication (i.e., synthesis of multiple − IgG + − Chronic hepatitis B, high infectivity copies of the viral genome) by PCR − IgG − + 1. Late acute or chronic hepatitis B, low infectivity or TMA, in which the viral RNA is 2. HBeAg-negative (“precore-mutant”) hepatitis B reverse transcribed to complemen(chronic or, rarely, acute) tary DNA and then amplified by + + + +/− +/− 1. HBsAg of one subtype and heterotypic anti-HBs repeated cycles of DNA synthesis. (common) Both can be used as quantitative 2. Process of seroconversion from HBsAg to anti-assays and a measurement of relative HBs (rare) “viral load”; PCR and TMA, with − − IgM +/− +/− 1. Acute hepatitis Ba a sensitivity of 10–102 IU/mL, are


InternalMed_Harrison

InternalMed_Harrison. Process of seroconversion from HBsAg to anti-assays and a measurement of relative HBs (rare) “viral load”; PCR and TMA, with − − IgM +/− +/− 1. Acute hepatitis Ba a sensitivity of 10–102 IU/mL, are more sensitive than bDNA, with a 2. Anti-HBc “window” sensitivity of 103 IU/mL; assays are − − IgG − +/− 1. Low-level hepatitis B carrier available with a wide dynamic range 2. Hepatitis B in remote past (10–107 IU/mL). Determination of


InternalMed_Harrison

InternalMed_Harrison. HCV RNA level is not a reliable − + − − − 1. Immunization with HBsAg (after vaccination) marker of disease severity or progno 2. Hepatitis B in the remote past (?) sis but is helpful in predicting relative 3. False-positive aIgM anti-HBc may reappear during acute reactivation of chronic hepatitis B. Note: See text for abbreviations.


InternalMed_Harrison

InternalMed_Harrison. amplification assays remain reactive well below the current 103–104 IU/ mL threshold for infectivity and liver injury. These markers are useful in following the course of HBV replication in patients with chronic hepatitis B receiving antiviral chemotherapy (Chap. 362). Except for the early decades of life after perinatally acquired HBV infection (see above), in immunocompetent adults with chronic hepatitis B, a general correlation exists between the level of HBV replication, as reflected by the level of serum HBV DNA, and the degree of liver injury. High-serum HBV DNA levels, increased expression of viral antigens, and necroinflammatory activity in the liver go hand in hand unless immunosuppression interferes with cytolytic T cell responses to virus-infected cells; reduction of HBV replication with antiviral drugs tends to be accompanied by an improvement in liver histology. Among patients with chronic hepatitis B, high levels of HBV DNA increase the risk of cirrhosis, hepatic


InternalMed_Harrison

InternalMed_Harrison. replication with antiviral drugs tends to be accompanied by an improvement in liver histology. Among patients with chronic hepatitis B, high levels of HBV DNA increase the risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma (see “Complications and Sequelae”).


InternalMed_Harrison

InternalMed_Harrison. In patients with hepatitis C, an episodic pattern of aminotransferase elevation is common. A specific serologic diagnosis of hepatitis C can be made by demonstrating the presence in serum of anti-HCV. When contemporary immunoassays are used, anti-HCV can be detected in acute hepatitis C during the initial phase of elevated aminotransferase activity and remains detectable after recovery (rare) and during chronic infection (common). Nonspecificity can confound immunoassays for anti-HCV, especially in persons with a low prior probability of infection, such as volunteer blood donors, or in persons with circulating rheumatoid factor, which can bind nonspecifically to assay reagents; testing for HCV RNA can be used in such settings to distinguish between true-positive and false-positive anti-HCV determinations. Assays for HCV RNA are the most sensitive tests for HCV infection and represent the “gold standard” in establishing a diagnosis of hepatitis C. HCV RNA can be detected even before


InternalMed_Harrison

InternalMed_Harrison. determinations. Assays for HCV RNA are the most sensitive tests for HCV infection and represent the “gold standard” in establishing a diagnosis of hepatitis C. HCV RNA can be detected even before acute elevation of aminotransferase activity and before the appearance of anti-HCV in patients with acute hepatitis C. In addition, HCV RNA remains detectable indefinitely, continuously in most but intermittently in some, in patients with chronic hepatitis C (detectable as well in some persons with normal liver tests, i.e., inactive carriers). In the very small minority of patients with hepatitis C who lack anti-HCV, a diagnosis can be supported by detection of HCV RNA. If all these tests are negative and the patient has a well-characterized case of hepatitis after percutaneous exposure to blood or blood products, a diagnosis of hepatitis caused by an unidentified agent can be entertained.


InternalMed_Harrison

InternalMed_Harrison. Amplification techniques are required to detect HCV RNA, and two types are available. One is a branched-chain complementary DNA (bDNA) assay, in which the detection signal (a colorimetrically responsiveness to antiviral therapy. The same is true for determinations of HCV genotype (Chap. 362). A proportion of patients with hepatitis C have isolated anti-HBc in their blood, a reflection of a common risk in certain populations of exposure to multiple bloodborne hepatitis agents. The anti-HBc in such cases is almost invariably of the IgG class and usually represents HBV infection in the remote past (HBV DNA undetectable); it rarely represents current HBV infection with low-level virus carriage.


InternalMed_Harrison

InternalMed_Harrison. The presence of HDV infection can be identified by demonstrating intrahepatic HDV antigen or, more practically, an anti-HDV seroconversion (a rise in titer of anti-HDV or de novo appearance of anti-HDV). Circulating HDV antigen, also diagnostic of acute infection, is detectable only briefly, if at all. Because anti-HDV is often undetectable once HBsAg disappears, retrospective serodiagnosis of acute self-limited, simultaneous HBV and HDV infection is difficult. Early diagnosis of acute infection may be hampered by a delay of up to 30–40 days in the appearance of anti-HDV.


InternalMed_Harrison

InternalMed_Harrison. When a patient presents with acute hepatitis and has HBsAg and anti-HDV in serum, determination of the class of anti-HBc is helpful in establishing the relationship between infection with HBV and HDV. Although IgM anti-HBc does not distinguish absolutely between acute and chronic HBV infection, its presence is a reliable indicator of recent infection and its absence a reliable indicator of infection in the remote past. In simultaneous acute HBV and HDV infections, IgM anti-HBc will be detectable, whereas in acute HDV infection superimposed on chronic HBV infection, anti-HBc will be of the IgG class. Tests for the presence of HDV RNA are useful for determining the presence of ongoing HDV replication and relative infectivity.


InternalMed_Harrison

InternalMed_Harrison. The serologic/virologic course of events during acute hepatitis E is entirely analogous to that of acute hepatitis A, with brief fecal shedding of virus and viremia and an early IgM anti-HEV response that predominates during approximately the first 3 months but is eclipsed thereafter by long-lasting IgG anti-HEV. Diagnostic tests of varying reliability for hepatitis E are commercially available but used routinely primarily outside the United States; in the United States, diagnostic serologic/virologic assays can be performed at the Centers for Disease Control and Prevention or other specialized reference laboratories. Liver biopsy is rarely necessary or indicated in acute viral hepatitis, except when the diagnosis is questionable or when clinical evidence suggests a diagnosis of chronic hepatitis.


InternalMed_Harrison

InternalMed_Harrison. Liver biopsy is rarely necessary or indicated in acute viral hepatitis, except when the diagnosis is questionable or when clinical evidence suggests a diagnosis of chronic hepatitis. A diagnostic algorithm can be applied in the evaluation of cases of acute viral hepatitis. A patient with acute hepatitis should undergo four serologic tests, HBsAg, IgM anti-HAV, IgM anti-HBc, and anti-HCV (Table 360-6). The presence of HBsAg, with or without IgM anti-HBc, represents HBV infection. If IgM anti-HBc is present, the HBV infection is considered acute; if IgM anti-HBc is absent, the HBV infection is considered chronic. A diagnosis of acute hepatitis B can be made in Serologic Tests of Patient’s Serum Note: See text for abbreviations.


InternalMed_Harrison

InternalMed_Harrison. Serologic Tests of Patient’s Serum Note: See text for abbreviations. the absence of HBsAg when IgM anti-HBc is detectable. A diagnosis of acute hepatitis A is based on the presence of IgM anti-HAV. If IgM anti-HAV coexists with HBsAg, a diagnosis of simultaneous HAV and HBV infections can be made; if IgM anti-HBc (with or without HBsAg) is detectable, the patient has simultaneous acute hepatitis A and B, and if IgM anti-HBc is undetectable, the patient has acute hepatitis A superimposed on chronic HBV infection. The presence of anti-HCV supports a diagnosis of acute hepatitis C. Occasionally, testing for HCV RNA or repeat anti-HCV testing later during the illness is necessary to establish the diagnosis. Absence of all serologic markers is consistent with a diagnosis of “non-A, non-B, non-C” hepatitis, if the epidemiologic setting is appropriate.


InternalMed_Harrison

InternalMed_Harrison. In patients with chronic hepatitis, initial testing should consist of HBsAg and anti-HCV. Anti-HCV supports and HCV RNA testing establishes the diagnosis of chronic hepatitis C. If a serologic diagnosis of chronic hepatitis B is made, testing for HBeAg and anti-HBe is indicated to evaluate relative infectivity. Testing for HBV DNA in such patients provides a more quantitative and sensitive measure of the level of virus replication and, therefore, is very helpful during antiviral therapy (Chap. 362). In patients with chronic hepatitis B and normal aminotransferase activity in the absence of HBeAg, serial testing over time is often required to distinguish between inactive carriage and HBeAg-negative chronic hepatitis B with fluctuating virologic and necroinflammatory activity. In persons with hepatitis B, testing for anti-HDV is useful in those with severe and fulminant disease, with severe chronic disease, with chronic hepatitis B and acute hepatitis-like exacerbations, with frequent


InternalMed_Harrison

InternalMed_Harrison. hepatitis B, testing for anti-HDV is useful in those with severe and fulminant disease, with severe chronic disease, with chronic hepatitis B and acute hepatitis-like exacerbations, with frequent percutaneous exposures, and from areas where HDV infection is endemic.


InternalMed_Harrison

InternalMed_Harrison. Virtually all previously healthy patients with hepatitis A recover completely with no clinical sequelae. Similarly, in acute hepatitis B, 95–99% of previously healthy adults have a favorable course and recover completely. Certain clinical and laboratory features, however, suggest a more complicated and protracted course. Patients of advanced age and with serious underlying medical disorders may have a prolonged course and are more likely to experience severe hepatitis. Initial presenting features such as ascites, peripheral edema, and symptoms of hepatic encephalopathy suggest a poorer prognosis. In addition, a prolonged PT, low serum albumin level, hypoglycemia, and very high serum bilirubin values suggest severe hepatocellular disease. Patients with these clinical and laboratory features deserve prompt hospital admission. The case fatality rate in hepatitis A and B is very low (~0.1%) but is increased by advanced age and underlying debilitating disorders. Among patients ill enough


InternalMed_Harrison

InternalMed_Harrison. deserve prompt hospital admission. The case fatality rate in hepatitis A and B is very low (~0.1%) but is increased by advanced age and underlying debilitating disorders. Among patients ill enough to be hospitalized for acute hepatitis B, the fatality rate is 1%. Hepatitis C is less severe during the acute phase than hepatitis B and is more likely to be anicteric; fatalities are rare, but the precise case fatality rate is not known. In outbreaks of waterborne hepatitis E in India and Asia, the case fatality rate is 1–2% and up to 10–20% in pregnant women. Contributing to fulminant hepatitis E in endemic countries are instances of acute hepatitis E superimposed on underlying chronic liver disease (“acute-on-chronic” liver disease). Patients with simultaneous acute hepatitis B and hepatitis D do not necessarily experience a higher mortality rate than do patients with acute hepatitis B alone; however, in several outbreaks of acute simultaneous HBV and HDV infection among injection drug


InternalMed_Harrison

InternalMed_Harrison. D do not necessarily experience a higher mortality rate than do patients with acute hepatitis B alone; however, in several outbreaks of acute simultaneous HBV and HDV infection among injection drug users, the case fatality rate was ~5%. When HDV superinfection occurs in a person with chronic hepatitis B, the likelihood of fulminant hepatitis and death is increased substantially. Although the case fatality rate for hepatitis D is not known definitively, in outbreaks of severe HDV superinfection in isolated populations with a high hepatitis B carrier rate, a mortality rate >20% has been recorded.


InternalMed_Harrison

InternalMed_Harrison. A small proportion of patients with hepatitis A experience relapsing hepatitis weeks to months after apparent recovery from acute hepatitis. Relapses are characterized by recurrence of symptoms, aminotransferase elevations, occasionally jaundice, and fecal excretion of HAV. Another unusual variant of acute hepatitis A is cholestatic hepatitis, characterized by protracted cholestatic jaundice and pruritus. Rarely, liver test abnormalities persist for many months, even up to a year. Even when these complications occur, hepatitis A remains self-limited and does not progress to chronic liver disease. During the prodromal phase of acute hepatitis B, a serum sickness–like syndrome characterized by arthralgia or arthritis, rash, angioedema, and rarely, hematuria and proteinuria may develop in 5–10% of patients. This syndrome occurs before the onset of clinical jaundice, and these patients are often diagnosed erroneously as having rheumatologic diseases. The diagnosis can be established by


InternalMed_Harrison

InternalMed_Harrison. 5–10% of patients. This syndrome occurs before the onset of clinical jaundice, and these patients are often diagnosed erroneously as having rheumatologic diseases. The diagnosis can be established by measuring serum aminotransferase levels, which are almost invariably elevated, and serum HBsAg. As noted above, EMC is an immune-complex disease that can complicate chronic hepatitis C and is part of a spectrum of B cell lymphoproliferative disorders, which, in rare instances, can evolve to B cell lymphoma (Chap. 134). Attention has been drawn as well to associations between hepatitis C and such cutaneous disorders as porphyria cutanea tarda and lichen planus. A mechanism for these associations is unknown. Finally, related to the reliance of HCV on lipoprotein secretion and assembly pathways and on interactions of HCV with glucose metabolism, HCV infection may be complicated by hepatic steatosis, hypercholesterolemia, insulin resistance (and other manifestations of the metabolic


InternalMed_Harrison

InternalMed_Harrison. pathways and on interactions of HCV with glucose metabolism, HCV infection may be complicated by hepatic steatosis, hypercholesterolemia, insulin resistance (and other manifestations of the metabolic syndrome), and type 2 diabetes mellitus; both hepatic steatosis and insulin resistance appear to accelerate hepatic fibrosis and blunt responsiveness to antiviral therapy (Chap. 362).


InternalMed_Harrison

InternalMed_Harrison. The most feared complication of viral hepatitis is fulminant hepatitis (massive hepatic necrosis); fortunately, this is a rare event. Fulminant hepatitis is seen primarily in hepatitis B, D, and E, but rare fulminant cases of hepatitis A occur primarily in older adults and in persons with underlying chronic liver disease, including, according to some reports, chronic hepatitis B and C. Hepatitis B accounts for >50% of fulminant cases of viral hepatitis, a sizable proportion of which are associated with HDV infection and another proportion with underlying chronic hepatitis C. Fulminant hepatitis is hardly ever seen in hepatitis C, but hepatitis E, as noted above, can be complicated by fatal fulminant hepatitis in 1–2% of all cases and in up to 20% of cases in pregnant women. Patients usually present with signs and symptoms of encephalopathy that may evolve to deep coma. The liver is usually small and the PT excessively prolonged. The combination of rapidly shrinking liver size, rapidly


InternalMed_Harrison

InternalMed_Harrison. present with signs and symptoms of encephalopathy that may evolve to deep coma. The liver is usually small and the PT excessively prolonged. The combination of rapidly shrinking liver size, rapidly rising bilirubin level, and marked prolongation of the PT, even as aminotransferase levels fall, together with clinical signs of confusion, disorientation, somnolence, ascites, and edema, indicates that the patient has hepatic failure with encephalopathy. Cerebral edema is common; brainstem compression, gastrointestinal bleeding, sepsis, respiratory failure, cardiovascular collapse, and renal failure are terminal events. The mortality rate is exceedingly high (>80% in patients with deep coma), but patients who survive may have a complete biochemical and histologic recovery. If a donor liver can be located in time, liver transplantation may be life-saving in patients with fulminant hepatitis (Chap. 368).


InternalMed_Harrison

InternalMed_Harrison. Documenting the disappearance of HBsAg after apparent clinical recovery from acute hepatitis B is particularly important. Before laboratory methods were available to distinguish between acute hepatitis and acute hepatitis-like exacerbations (spontaneous reactivations) of chronic hepatitis B, observations suggested that ~10% of previously healthy patients remained HBsAg-positive for >6 months after the onset of clinically apparent acute hepatitis B. One-half of these persons cleared the antigen from their circulations during the next several years, but the other 5% remained chronically HBsAg-positive. More recent observations suggest that the true rate of chronic infection after clinically apparent acute hepatitis B is as low as 1% in normal, immunocompetent, young adults. Earlier, higher estimates may have been confounded by inadvertent inclusion of acute exacerbations in chronically infected patients; these patients, chronically HBsAg-positive before exacerbation, were unlikely to


InternalMed_Harrison

InternalMed_Harrison. estimates may have been confounded by inadvertent inclusion of acute exacerbations in chronically infected patients; these patients, chronically HBsAg-positive before exacerbation, were unlikely to seroconvert to HBsAg-negative thereafter. Whether the rate of chronicity is 10% or 1%, such patients have IgG anti-HBc in serum; anti-HBs is either undetected or detected at low titer against the opposite subtype specificity of the antigen (see “Laboratory Features”). These patients may (1) be inactive carriers; (2) have low-grade, mild chronic hepatitis; or (3) have moderate to severe chronic hepatitis with or without cirrhosis. The likelihood of remaining chronically infected after acute HBV infection is especially high among neonates, persons with Down’s syndrome, chronically hemodialyzed patients, and immunosuppressed patients, including persons with HIV infection.


InternalMed_Harrison

InternalMed_Harrison. Chronic hepatitis is an important late complication of acute hepatitis B occurring in a small proportion of patients with acute disease but more common in those who present with chronic infection without having experienced an acute illness, as occurs typically after neonatal infection or after infection in an immunosuppressed host (Chap. 362). The following clinical and laboratory features suggest progression of acute hepatitis to chronic hepatitis: (1) lack of complete resolution of clinical symptoms of anorexia, weight loss, fatigue, and the persistence of hepatomegaly; (2) the presence of bridging/interface or multilobular hepatic necrosis on liver biopsy during protracted, severe acute viral hepatitis; (3) failure of the serum aminotransferase, bilirubin, and globulin levels to return to normal within 6–12 months after the acute illness; and (4) the persistence of HBeAg for >3 months or HBsAg for >6 months after acute hepatitis.


InternalMed_Harrison

InternalMed_Harrison. Although acute hepatitis D infection does not increase the likelihood of chronicity of simultaneous acute hepatitis B, hepatitis D has the potential for contributing to the severity of chronic hepatitis B. Hepatitis D superinfection can transform inactive or mild chronic hepatitis B into severe, progressive chronic hepatitis and cirrhosis; it also can accelerate the course of chronic hepatitis B. Some HDV superinfections in patients with chronic hepatitis B lead to fulminant hepatitis. As defined in longitudinal studies over three decades, the annual rates of cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis D are 4% and 2.8%, respectively. Although HDV and HBV infections are associated with severe liver disease, mild hepatitis and even inactive carriage have been identified in some patients, and the disease may become indolent beyond the early years of infection.


InternalMed_Harrison

InternalMed_Harrison. After acute HCV infection, the likelihood of remaining chronically infected approaches 85–90%. Although many patients with chronic hepatitis C have no symptoms, cirrhosis may develop in as many as 20% within 10–20 years of acute illness; in some series of cases reported by referral centers, cirrhosis has been reported in as many as 50% of patients with chronic hepatitis C. Although chronic hepatitis C accounts for at least 40% of cases of chronic liver disease and of patients undergoing liver transplantation for end-stage liver disease in the United States and Europe, in the majority of patients with chronic hepatitis C, morbidity and mortality are limited during the initial 20 years after the onset of infection. Progression of chronic hepatitis C may be influenced by advanced age of acquisition, long duration of infection, immunosuppression, coexisting excessive alcohol use, concomitant hepatic steatosis, other hepatitis virus infection, or HIV co-infection. In fact, instances of


InternalMed_Harrison

InternalMed_Harrison. long duration of infection, immunosuppression, coexisting excessive alcohol use, concomitant hepatic steatosis, other hepatitis virus infection, or HIV co-infection. In fact, instances of severe and rapidly progressive chronic hepatitis B and C are being recognized with increasing frequency in patients with HIV infection (Chap. 226). In contrast, neither HAV nor HEV causes chronic liver disease in immunocompetent hosts; 2019 however, cases of chronic hepatitis E have been observed in immunosuppressed organ-transplant recipients, persons receiving cytotoxic chemotherapy, and persons with HIV infection.


InternalMed_Harrison

InternalMed_Harrison. Rare complications of viral hepatitis include pancreatitis, myocarditis, atypical pneumonia, aplastic anemia, transverse myelitis, and peripheral neuropathy. Persons with chronic hepatitis B, particularly those infected in infancy or early childhood and especially those with HBeAg and/or high-level HBV DNA, have an enhanced risk of hepatocellular carcinoma. The risk of hepatocellular carcinoma is increased as well in patients with chronic hepatitis C, almost exclusively in patients with cirrhosis, and almost always after at least several decades, usually after three decades of disease (Chap. 111). In children, hepatitis B may present rarely with anicteric hepatitis, a nonpruritic papular rash of the face, buttocks, and limbs, and lymphadenopathy (papular acrodermatitis of childhood or Gianotti-Crosti syndrome). Rarely, autoimmune hepatitis (Chap. 362) can be triggered by a bout of otherwise self-limited acute hepatitis, as reported after acute hepatitis A, B, and C.


InternalMed_Harrison

InternalMed_Harrison. Viral diseases such as infectious mononucleosis; those due to cytomegalovirus, herpes simplex, and coxsackieviruses; and toxoplasmosis may share certain clinical features with viral hepatitis and cause elevations in serum aminotransferase and, less commonly, in serum bilirubin levels. Tests such as the differential heterophile and serologic tests for these agents may be helpful in the differential diagnosis if HBsAg, anti-HBc, IgM anti-HAV, and anti-HCV determinations are negative. Aminotransferase elevations can accompany almost any systemic viral infection; other rare causes of liver injury confused with viral hepatitis are infections with Leptospira, Candida, Brucella, Mycobacteria, and Pneumocystis. A complete drug history is particularly important because many drugs and certain anesthetic agents can produce a picture of either acute hepatitis or cholestasis (Chap. 361). Equally important is a past history of unexplained “repeated episodes” of acute hepatitis. This history should


InternalMed_Harrison

InternalMed_Harrison. agents can produce a picture of either acute hepatitis or cholestasis (Chap. 361). Equally important is a past history of unexplained “repeated episodes” of acute hepatitis. This history should alert the physician to the possibility that the underlying disorder is chronic hepatitis. Alcoholic hepatitis must also be considered, but usually the serum aminotransferase levels are not as markedly elevated, and other stigmata of alcoholism may be present. The finding on liver biopsy of fatty infiltration, a neutrophilic inflammatory reaction, and “alcoholic hyaline” would be consistent with alcohol-induced rather than viral liver injury. Because acute hepatitis may present with right upper quadrant abdominal pain, nausea and vomiting, fever, and icterus, it is often confused with acute cholecystitis, common duct stone, or ascending cholangitis. Patients with acute viral hepatitis may tolerate surgery poorly; therefore, it is important to exclude this diagnosis, and in confusing cases, a


InternalMed_Harrison

InternalMed_Harrison. common duct stone, or ascending cholangitis. Patients with acute viral hepatitis may tolerate surgery poorly; therefore, it is important to exclude this diagnosis, and in confusing cases, a percutaneous liver biopsy may be necessary before laparotomy. Viral hepatitis in the elderly is often misdiagnosed as obstructive jaundice resulting from a common duct stone or carcinoma of the pancreas. Because acute hepatitis in the elderly may be quite severe and the operative mortality high, a thorough evaluation including biochemical tests, radiographic studies of the biliary tree, and even liver biopsy may be necessary to exclude primary parenchymal liver disease. Another clinical constellation that may mimic acute hepatitis is right ventricular failure with passive hepatic congestion or hypoperfusion syndromes, such as those associated with shock, severe hypotension, and severe left ventricular failure. Also included in this general category is any disorder that interferes with venous return


InternalMed_Harrison

InternalMed_Harrison. syndromes, such as those associated with shock, severe hypotension, and severe left ventricular failure. Also included in this general category is any disorder that interferes with venous return to the heart, such as right atrial myxoma, constrictive pericarditis, hepatic vein occlusion (Budd-Chiari syndrome), or venoocclusive disease. Clinical features are usually sufficient to distinguish among these vascular disorders and viral hepatitis. Acute fatty liver of pregnancy, cholestasis of pregnancy, eclampsia, and the HELLP (h emolysis, e levated l iver tests, and l ow p latelets) syndrome can be confused with viral hepatitis during pregnancy. Very rarely, malignancies metastatic to the liver can mimic acute or even fulminant viral hepatitis. Occasionally, genetic or metabolic liver disorders (e.g., Wilson’s disease, α1 antitrypsin deficiency) and nonalcoholic fatty liver disease are confused with acute viral hepatitis.


InternalMed_Harrison

InternalMed_Harrison. In hepatitis B, among previously healthy adults who present with clinically apparent acute hepatitis, recovery occurs in ~99%; therefore, antiviral therapy is not likely to improve the rate of recovery and is not required. In rare instances of severe acute hepatitis B, treatment with a nucleoside analogue at oral doses used to treat chronic hepatitis B (Chap. 362) has been attempted successfully. Although clinical trials have not been done to establish the efficacy or duration of this approach, most authorities would recommend institution of antiviral therapy with a nucleoside analogue (entecavir or tenofovir, the most potent and least resistance-prone agents) for severe, but not mild–moderate, acute hepatitis B. Treatment should continue until 3 months after HBsAg seroconversion or 6 months after HBeAg seroconversion.


InternalMed_Harrison

InternalMed_Harrison. In typical cases of acute hepatitis C, recovery is rare, progression to chronic hepatitis is the rule, and meta-analyses of small clinical trials suggest that antiviral therapy with interferon α monotherapy (3 million units SC three times a week) is beneficial, reducing the rate of chronicity considerably by inducing sustained responses in 30–70% of patients. In a German multicenter study of 44 patients with acute symptomatic hepatitis C, initiation of intensive interferon α therapy (5 million units SC daily for 4 weeks, then three times a week for another 20 weeks) within an average of 3 months after infection resulted in a sustained virologic response rate of 98%. Although treatment of acute hepatitis C is recommended, the optimum regimen, duration of therapy, and time to initiate therapy remain to be determined. Many authorities now opt for a 24-week course (beginning within 2–3 months after onset) of long-acting pegylated interferon plus the nucleoside analogue ribavirin, although


InternalMed_Harrison

InternalMed_Harrison. remain to be determined. Many authorities now opt for a 24-week course (beginning within 2–3 months after onset) of long-acting pegylated interferon plus the nucleoside analogue ribavirin, although the value of adding ribavirin has not been demonstrated (see Chap. 362 for doses). Patients with jaundice and women are more likely to recover from acute hepatitis C, and now that genetic markers associated with spontaneous recovery (IL28B CC haplotype) versus persistence (non-CC haplotypes) have been defined, such genetic testing can help determine the need for and immediacy of treating acute hepatitis C—maintaining a high threshold for treating patients with CC and a very low threshold for early intervention in patients with non-CC genotypes. Protease inhibitor–based antiviral therapy with telaprevir or boceprevir, now approved for chronic hepatitis C, genotype 1 (Chap. 362), has not been approved for acute hepatitis C. Moreover, given the high efficacy of pegylated interferon–based


InternalMed_Harrison

InternalMed_Harrison. telaprevir or boceprevir, now approved for chronic hepatitis C, genotype 1 (Chap. 362), has not been approved for acute hepatitis C. Moreover, given the high efficacy of pegylated interferon–based therapy for acute hepatitis C, in all likelihood, the addition of a protease inhibitor would add costs and side effects without incremental efficacy. When, however, after 2014, all-oral, brief-duration, low-resistance antiviral regimens replace the current standard of care, the new approaches will be applied to acute hepatitis C and, potentially (pending the outcome of clinical trials), could even be used immediately after exposure (e.g., occupational) to prevent infection and the onset of hepatitis. Because of the marked reduction over the past two decades in the frequency of acute hepatitis C, opportunities to identify and treat patients with acute hepatitis C are rare, except in injection drug users and health workers who sustain hepatitis C–contaminated needle sticks. After such


InternalMed_Harrison

InternalMed_Harrison. C, opportunities to identify and treat patients with acute hepatitis C are rare, except in injection drug users and health workers who sustain hepatitis C–contaminated needle sticks. After such occupational accidents, when monitoring for ALT elevations and the presence of HCV RNA identifies acute hepatitis C (risk only ~3%), therapy should be initiated.


InternalMed_Harrison

InternalMed_Harrison. Notwithstanding these specific therapeutic considerations, in most cases of typical acute viral hepatitis, specific treatment generally is not necessary. Although hospitalization may be required for clinically severe illness, most patients do not require hospital care. Forced and prolonged bed rest is not essential for full recovery, but many patients will feel better with restricted physical activity. A high-calorie diet is desirable, and because many patients may experience nausea late in the day, the major caloric intake is best tolerated in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot maintain oral intake. Drugs capable of producing adverse reactions such as cholestasis and drugs metabolized by the liver should be avoided. If severe pruritus is present, the use of the bile salt-sequestering resin cholestyramine is helpful. Glucocorticoid therapy has no value in acute viral hepatitis, even in severe cases


InternalMed_Harrison

InternalMed_Harrison. be avoided. If severe pruritus is present, the use of the bile salt-sequestering resin cholestyramine is helpful. Glucocorticoid therapy has no value in acute viral hepatitis, even in severe cases associated with bridging necrosis, and may be deleterious, even increasing the risk of chronicity (e.g., of acute hepatitis B).


InternalMed_Harrison

InternalMed_Harrison. Physical isolation of patients with hepatitis to a single room and bathroom is rarely necessary except in the case of fecal incontinence for hepatitis A and E or uncontrolled, voluminous bleeding for hepatitis B (with or without concomitant hepatitis D) and hepatitis C. Because most patients hospitalized with hepatitis A excrete little, if any, HAV, the likelihood of HAV transmission from these patients during their hospitalization is low. Therefore, burdensome enteric precautions are no longer recommended. Although gloves should be worn when the bed pans or fecal material of patients with hepatitis A are handled, these precautions do not represent a departure from sensible procedure and contemporary universal precautions for all hospitalized patients. For patients with hepatitis B and hepatitis C, emphasis should be placed on blood precautions (i.e., avoiding direct, ungloved hand contact with blood and other body fluids). Enteric precautions are unnecessary. The importance of simple


InternalMed_Harrison

InternalMed_Harrison. C, emphasis should be placed on blood precautions (i.e., avoiding direct, ungloved hand contact with blood and other body fluids). Enteric precautions are unnecessary. The importance of simple hygienic precautions such as hand washing cannot be overemphasized. Universal precautions that have been adopted for all patients apply to patients with viral hepatitis. Hospitalized patients may be discharged following substantial symptomatic improvement, a significant downward trend in the serum aminotransferase and bilirubin values, and a return to normal of the PT. Mild aminotransferase elevations should not be considered contraindications to the gradual resumption of normal activity.


InternalMed_Harrison

InternalMed_Harrison. In fulminant hepatitis, the goal of therapy is to support the patient by maintenance of fluid balance, support of circulation and respiration, control of bleeding, correction of hypoglycemia, and treatment of other complications of the comatose state in anticipation of liver regeneration and repair. Protein intake should be restricted, and oral lactulose or neomycin administered. Glucocorticoid therapy has been shown in controlled trials to be ineffective. Likewise, exchange transfusion, plasmapheresis, human cross-circulation, porcine liver cross-perfusion, hemoperfusion, and extracorporeal liver-assist devices have not been proven to enhance survival. Meticulous intensive care that includes prophylactic antibiotic coverage is the one factor that does appear to improve survival. Orthotopic liver transplantation is resorted to with increasing frequency, with excellent results, in patients with fulminant hepatitis (Chap. 368).


InternalMed_Harrison

InternalMed_Harrison. Because application of therapy for acute viral hepatitis is limited and because antiviral therapy for chronic viral hepatitis is cumbersome, costly, and not effective in all patients (Chap. 362), emphasis is placed on prevention through immunization. The prophylactic approach differs for each of the types of viral hepatitis. In the past, immunoprophylaxis relied exclusively on passive immunization with antibody-containing globulin preparations purified by cold ethanol fractionation from the plasma of hundreds of normal donors. Currently, for hepatitis A, B, and E, active immunization with vaccines is the preferable approach to prevention.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis A Both passive immunization with IG and active immunization with killed vaccines are available. All preparations of IG contain anti-HAV concentrations sufficient to be protective. When administered before exposure or during the early incubation period, IG is effective in preventing clinically apparent hepatitis A. For postexposure prophylaxis of intimate contacts (household, sexual, institutional) of persons with hepatitis A, the administration of 0.02 mL/kg is recommended as early after exposure as possible; it may be effective even when administered as late as 2 weeks after exposure. Prophylaxis is not necessary for those who have already received hepatitis A vaccine, for casual contacts (office, factory, school, or hospital), for most elderly persons, who are very likely to be immune, or for those known to have anti-HAV in their serum. In day care centers, recognition of hepatitis A in children or staff should provide a stimulus for immunoprophylaxis in the center and in


InternalMed_Harrison

InternalMed_Harrison. immune, or for those known to have anti-HAV in their serum. In day care centers, recognition of hepatitis A in children or staff should provide a stimulus for immunoprophylaxis in the center and in the children’s family members. By the time most common-source outbreaks of hepatitis A are recognized, it is usually too late in the incubation period for IG to be effective; however, prophylaxis may limit the frequency of secondary cases. For travelers to tropical countries, developing countries, and other areas outside standard tourist routes, IG prophylaxis had been recommended before a vaccine became available. When such travel lasted <3 months, 0.02 mL/ kg was given; for longer travel or residence in these areas, a dose of 0.06 mL/kg every 4–6 months was recommended. Administration of plasma-derived globulin is safe; all contemporary lots of IG are subjected to viral inactivation steps and must be free of HCV RNA as determined by PCR testing. Administration of IM lots of IG has not


InternalMed_Harrison

InternalMed_Harrison. globulin is safe; all contemporary lots of IG are subjected to viral inactivation steps and must be free of HCV RNA as determined by PCR testing. Administration of IM lots of IG has not been associated with transmission of HBV, HCV, or HIV.


InternalMed_Harrison

InternalMed_Harrison. Formalin-inactivated vaccines made from strains of HAV attenuated in tissue culture have been shown to be safe, immunogenic, and effective in preventing hepatitis A. Hepatitis A vaccines are approved for use in persons who are at least 1 year old and appear to provide adequate protection beginning 4 weeks after a primary inoculation. If it can be given within 4 weeks of an expected exposure, such as by travel to an endemic area, hepatitis A vaccine is the preferred approach to pre-exposure immunoprophylaxis. If travel is more imminent, IG (0.02 mL/kg) should be administered at a different injection site, along with the first dose of vaccine. Because vaccination provides long-lasting protection (protective levels of anti-HAV should last 20 years after vaccination), persons whose risk will be sustained (e.g., frequent travelers or those remaining in endemic areas for prolonged periods) should be vaccinated, and vaccine should supplant the need for repeated IG injections. Shortly after


InternalMed_Harrison

InternalMed_Harrison. be sustained (e.g., frequent travelers or those remaining in endemic areas for prolonged periods) should be vaccinated, and vaccine should supplant the need for repeated IG injections. Shortly after its introduction, hepatitis A vaccine was recommended for children living in communities with a high incidence of HAV infection; in 1999, this recommendation was extended to include all children living in states, counties, and communities with high rates of HAV infection. As of 2006, the Advisory Committee on Immunization Practices of the U.S. Public Health Service recommended routine hepatitis A vaccination of all children. Other groups considered to be at increased risk for HAV infection and who are candidates for hepatitis A vaccination include military personnel, populations with cyclic outbreaks of hepatitis A (e.g., Alaskan natives), employees of day care centers, primate handlers, laboratory workers exposed to hepatitis A or fecal specimens, and patients with chronic liver disease.


InternalMed_Harrison

InternalMed_Harrison. of hepatitis A (e.g., Alaskan natives), employees of day care centers, primate handlers, laboratory workers exposed to hepatitis A or fecal specimens, and patients with chronic liver disease. Because of an increased risk of fulminant hepatitis A—observed in some experiences but not confirmed in others—among patients with chronic hepatitis C, patients with chronic hepatitis C are candidates for hepatitis A vaccination, as are persons with chronic hepatitis B. Other populations whose recognized risk of hepatitis A is increased should be vaccinated, including men who have sex with men, injection drug users, persons with clotting disorders who require frequent administration of clotting-factor concentrates, persons traveling from the United States to countries with high or intermediate hepatitis A endemicity, postexposure prophylaxis for contacts of persons with hepatitis A, and household members and other close contacts of adopted children arriving from countries with high and moderate


InternalMed_Harrison

InternalMed_Harrison. A endemicity, postexposure prophylaxis for contacts of persons with hepatitis A, and household members and other close contacts of adopted children arriving from countries with high and moderate hepatitis A endemicity. Recommendations for dose and frequency differ for the two approved vaccine preparations (Table 360-7); all injections are IM. Hepatitis A vaccine has been reported to be effective in preventing secondary household and day care center–associated cases of acute hepatitis A. Because the vaccine 1–18 2 25 units (0.5 mL) 0, 6–18 ≥19 2 50 units (1 mL) 0, 6–18 aA combination of this hepatitis A vaccine and hepatitis B vaccine, TWINRIX, is licensed for simultaneous protection against both of these viruses among adults (age ≥18 years). Each 1-mL dose contains 720 ELU of hepatitis A vaccine and 20 μg of hepatitis B vaccine. These doses are recommended at months 0, 1, and 6. bEnzyme-linked immunoassay units.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: ELU, enzyme-linked immunoassay unit. provides long-lasting protection and is simpler to use, in 2006, the 2021 Immunization Practices Advisory Committee of the U.S. Public Health Service favored hepatitis A vaccine to IG for postexposure prophylaxis of healthy persons age 2–40 years; for younger or older persons, for immunosuppressed patients, and for patients with chronic liver disease, IG should continue to be used. In the United States, reported mortality resulting from hepatitis A declined in parallel with hepatitis A vaccine– associated reductions in the annual incidence of new infections.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis B Until 1982, prevention of hepatitis B was based on passive immunoprophylaxis either with standard Ig, containing modest levels of anti-HBs, or hepatitis B immunoglobulin (HBIG), containing high-titer anti-HBs. The efficacy of standard IG has never been established and remains questionable; even the efficacy of HBIG, demonstrated in several clinical trials, has been challenged, and its contribution appears to be in reducing the frequency of clinical illness, not in preventing infection. The first vaccine for active immunization, introduced in 1982, was prepared from purified, noninfectious 22-nm spherical


InternalMed_Harrison

InternalMed_Harrison. HBsAg particles derived from the plasma of healthy HBsAg carriers. In 1987, the plasma-derived vaccine was supplanted by a genetically engineered vaccine derived from recombinant yeast. The latter vaccine consists of HBsAg particles that are nonglycosylated but are otherwise indistinguishable from natural HBsAg; two recombinant vaccines are licensed for use in the United States. Current recommendations can be divided into those for pre-exposure and postexposure prophylaxis.