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Glomerulonephritis with the nephrotic syndrome is observed occasionally; HBsAg, immunoglobulin, and C3 deposition has been found in the glomerular basement membrane. In these patients, the affected small- and medium-size arterioles contain HBsAg, immunoglobulins, and complement components. Another extrahepatic manifestation of viral hepatitis, essential mixed cryoglobulinemia EMC , was reported initially to be associated with hepatitis 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. 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. Immune-complex disorders have been linked, albeit rarely, with both hepatitis A and E. 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. 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. 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. A more severe histologic lesion, bridging hepatic necrosis , also termed subacute or confluent necrosis or interface hepatitis , is observed occasionally in acute hepatitis. 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.

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.

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. 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 The most accurate means to distinguish the various types of viral hepatitis involves specific serologic testing.

Pegylated interferon ribavirin. See text for other abbreviations. 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 e.

Intrafamily and intrainstitutional spreads 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 5пїЅ20 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.

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 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 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 пїЅ U. While universal childhood vaccination accounted for a high prevalence of vaccine-induced immunity in children aged 2пїЅ19 years, the lowest age-specific prevalence of anti-HAV This is a subgroup of the population who remain susceptible to acute hepatitis A acquired during travel to endemic areas and from contaminated foods, especially those imported from endemic countries.

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 infected persons, and at least some of these body fluidsпїЅmost notably semen and salivaпїЅare 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. 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. In most cases, acute infection in the neonate is clinically asymptomatic, but the child is very likely to remain chronically infected.

Whereas serum HBsAg is infrequent 0. 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. Because of highly sensitive virologic screening of donor blood, the risk of acquiring HBV infection from a blood transfusion is 1 in , 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.

In the United States, as demonstrated in NHANES пїЅ, following the implementation of universal childhood vaccination, HBsAg seropositivity had declined in children aged 6пїЅ19 years to as low as 0. Populations and groups for whom HBV infection screening is recommended are listed in Table Persons who are the source of blood or body fluids that would be an indication for postexposure prophylaxis e.

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 where hepatitis D is rare among persons with chronic hepatitis B and northern Europe, HDV infection is confined to persons exposed frequently to blood and blood products, primarily injection drug users, especially so in HIV-infected 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 South American villages e. Ultimately, such outbreaks of hepatitis DпїЅeither of co-infections with acute hepatitis B or of superinfections in those already infected with HBVпїЅmay blur the distinctions between endemic and nonendemic areas.

On a global scale, HDV infection declined at the end of the s. Still, the frequency of HDV infection during the first decade of the twenty-first century has not fallen below levels reached during the s; the reservoir has been sustained by survivors infected during пїЅ and recent immigrants from still-endemic e.

Routine screening of blood donors for HBsAg and the elimination of commercial blood sources in the early s reduced the frequency of, but did not eliminate, transfusion-associated hepatitis.

A prospective analysis of transfusion-associated hepatitis conducted between and showed that the frequency of transfusion-associated hepatitis at one urban university hospital fell from a baseline of 3.

The introduction of second-generation anti-HCV assays reduced the frequency of transfusion-associated hepatitis C to almost imperceptible levelsпїЅ1 in ,пїЅand 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.

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. 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 preparations for intravenous but not intramuscular use.

Moreover, such population surveys do not include higher-risk groups such as incarcerated persons, homeless persons, and active injection drug users, indicating that the actual prevalence is even higher. The high frequency in Egypt is attributable to contaminated equipment used for medical procedures and unsafe injection practices in the s to s during a campaign to eradicate schistosomiasis with intravenous tartar emetic.

Data from NHANES showed that between and , to year-old men had the highest prevalence of HCV infection; however, in a survey conducted between and , the peak age decile had shifted to those age 40пїЅ49 years; an increase in hepatitis CпїЅrelated mortality has paralleled this secular trend, increasing since predominantly in the to year age group. Thus, HCV was amplified iatrogenically not only in Egypt but also in the United States; in the United States, the seeds sewn by medical procedures in the s were reaped in the s and s among transfusion recipients and injection drug users, even those whose drug use was confined to brief adolescent experimentation.

Therefore, in , the Centers for Disease Control and Prevention recommended that all persons born between and be screened for hepatitis C, without ascertainment of risk, a recommendation shown to be cost-effective and predicted to identify , infected persons. The distribution of HCV genotypes varies in different parts of the world.

Worldwide, genotype 1 is the most common. As a bloodborne infection, HCV potentially can be transmitted sexually and perinatally; however, both of these modes of transmission are inefficient for hepatitis C.

Moreover, sexual transmission appears to be confined to such subgroups as persons with multiple sexual partners and sexually transmitted diseases; for example, isolated clusters of sexually transmitted HCV infection have been reported in HIV-infected men who have sex with men.

Breast-feeding does not increase the risk of HCV infection between an infected mother and her infant. Infection of household contacts is rare as well. Besides persons born between and , other groups with an increased frequency of HCV infection are listed in Table Although new acute cases of hepatitis C are rare outside of the injection-drug using community, 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 , amplified by the recent epidemic of opioid use, in a new cohort of young injection drug users, age 15пїЅ24 years accounting for more than two-thirds of all acute cases , who, unlike older cohorts, had not learned to take precautions to prevent bloodborne infections.

Health care, public safety, and emergency medical personnel following needle injury or mucosal exposure to HCV-contaminated blood. 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.

Evidence supports a zoonotic reservoir for HEV primarily in swine, which may account for the mostly subclinical infections in nonendemic areas. A previously unrecognized high distribution of HEV infection, linked to pork-product ingestion, has been discovered in western Europe e.

Acute viral hepatitis occurs after an incubation period that varies according to the responsible agent. Generally, incubation periods for hepatitis A range from 15 to 45 days mean, 4 weeks , for hepatitis B and D from 30 to days mean, 8пїЅ12 weeks , for hepatitis C from 15 to days mean, 7 weeks , and for hepatitis E from 14 to 60 days mean, 5пїЅ6 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 1пїЅ2 weeks.

The nausea, vomiting, and anorexia are frequently associated with alterations in olfaction and taste. Dark urine and clay-colored stools may be noticed by the patient from 1пїЅ5 days before the onset of clinical jaundice. With the onset of clinical jaundice , the constitutional prodromal symptoms usually diminish, but in some patients, mild weight loss 2. 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. 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 to 12 weeks, and is usually more prolonged in acute hepatitis B and C. In the remainder, biochemical recovery may be delayed. A substantial proportion of patients with viral hepatitis never become icteric. When acute HDV and HBV infections occur simultaneously, clinical and biochemical features may be indistinguishable from those of HBV infection alone, although occasionally they are 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 agents, acute hepatitis-like clinical events in persons with chronic hepatitis B may accompany spontaneous HBeAg to anti-HBe seroconversion or spontaneous reactivation i. The level of these enzymes, however, does not correlate well with the degree of liver cell damage. The diagnosis of anicteric hepatitis is based on clinical features and on aminotransferase elevations.

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.

In certain patients with underlying hemolytic anemia, however, such as glucosephosphate dehydrogenase deficiency and sickle cell anemia, a high serum bilirubin level is common, resulting from superimposed hemolysis. Neutropenia and lymphopenia are transient and are followed by a relative lymphocytosis. 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. 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.

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 serologic markers of diagnostic importance. 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. Rheumatoid factor can give rise to false-positive results in this test. 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. 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.

In immunocompetent persons, however, a correlation exists between markers of HBV replication and liver injury see below. Another important serologic marker in patients with hepatitis B is HBeAg. Its principal clinical usefulness is as an indicator of relative infectivity. In patients with hepatitis B surface antigenemia of unknown duration e. A false-positive test for IgM anti-HBc may be encountered in patients with high-titer rheumatoid factor. This antibody is directed not against the common group determinant, a , but against the heterotypic subtype determinant e.

In most cases, this serologic pattern cannot be attributed to infection with two different HBV subtypes but, instead, is thought based on the clonal selection theory of antibody diversity to reflect the stimulation of a related clone of antibody-forming cells and is not a harbinger of imminent HBsAg clearance. 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 These markers are useful in following the course of HBV replication in patients with chronic hepatitis B receiving antiviral chemotherapy Chap.

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. 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.

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.

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. Currently, such target amplification i. Determination of HCV RNA level is not a reliable marker of disease severity or prognosis but is helpful in predicting relative responsiveness to antiviral therapy.

The same is true for determinations of HCV genotype Chap. Of course, HCV RNA monitoring during and after antiviral therapy is the sine qua non for determining on-treatment and durable responsiveness.

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.

Circulating HDV antigen, also diagnostic of acute infection, is detectable only briefly, if at all. Early diagnosis of acute infection may be hampered by a delay of up to 30пїЅ40 days in the appearance of anti-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.

Assays for HDV RNA, available in specialized laboratories and yet to be standardized, can be used to confirm HDV infection and to monitor treatment during chronic infection. 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. The presence of anti-HCV supports a diagnosis of acute 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. 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 percutaneous exposures, and from areas where HDV infection is endemic. Virtually all previously healthy patients with hepatitis A recover completely with no clinical sequelae. 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. 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.

When HDV superinfection occurs in a person with chronic hepatitis B, the likelihood of fulminant hepatitis and death is increased substantially. 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, occasional 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 1 year. Even when these complications occur, hepatitis A remains self-limited and does not progress to chronic liver disease. 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.

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 syndrome , and type 2 diabetes mellitus; both hepatic steatosis and insulin resistance appear to accelerate hepatic fibrosis and blunt responsiveness to interferon-based antiviral therapy Chap.

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.

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 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. If a donor liver can be located in time, liver transplantation may be lifesaving in patients with fulminant hepatitis Chap.

Documenting the disappearance of HBsAg after apparent clinical recovery from acute hepatitis B is particularly important. 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 seroconvert to HBsAg-negative thereafter. 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.

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. 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. 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.

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 severe and rapidly progressive chronic hepatitis B and C are being recognized with increasing frequency in patients with HIV infection Chap.

In contrast, neither HAV nor HEV causes chronic liver disease in immunocompetent hosts; however, cases of chronic hepatitis E including cirrhosis and end-stage liver disease have been observed in immunosuppressed organ-transplant recipients, persons receiving cytotoxic chemotherapy, and persons with HIV infection.

Among patients with chronic hepatitis e. The risks of cirrhosis and hepatocellular carcinoma increase with the level of HBV replication. 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. Rare complications of viral hepatitis include pancreatitis, myocarditis, atypical pneumonia, aplastic anemia, transverse myelitis, and peripheral neuropathy.

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. 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.

Aminotransferase elevations can accompany almost any systemic viral infection; other rare causes of liver injury confused with viral hepatitis are infections with Leptospira , Candida , Brucell a , 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.

This history should alert the physician to the possibility that the underlying disorder is chronic hepatitis, for example autoimmune hepatitis Chap.

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. 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 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 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.

In rare instances of severe acute hepatitis B, treatment with a nucleoside analogue at oral doses used to treat chronic hepatitis B Chap. 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 mildпїЅmoderate, acute hepatitis B.

Although the duration of therapy for acute hepatitis C has not been determined definitively, in a study of 20 patients, acute hepatitis C resolved after treatment lasting only 6 weeks. Because spontaneous recovery can occur and because most cases of acute hepatitis C are not clinically severe or rapidly progressive, delaying antiviral therapy of acute hepatitis C for at least 12пїЅ16 weeks and even up to 6 months after which recovery is unlikely is a recommended approach. Such patients are candidates for antiviral therapy, and efforts to combine antiviral therapy with drug-rehabilitation therapy have been very successful.

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, and may be deleterious, even increasing the risk of chronicity e. 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 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 C, emphasis should be placed on blood precautions i.

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. 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 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 appears to improve survival. Orthotopic liver transplantation is resorted to with increasing frequency, with excellent results, in patients with fulminant hepatitis Chap.

Fulminant hepatitis C is very rare; however, in fulminant hepatitis B, oral antiviral therapy has been used successfully, as reported anecdotally. 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. 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. Both passive immunization with IG and active immunization with killed vaccines are available.

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. 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.

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.

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 preexposure immunoprophylaxis.

If travel is more imminent, IG 0. Because vaccination provides long-lasting protection protective levels of anti-HAV should last 20 years after vaccination , persons whose risk will be sustained e.

Shortly after its introduction, hepatitis A vaccine was recommended for children living in communities with a high incidence of HAV infection; in , this recommendation was extended to include all children living in states, counties, and communities with high rates of HAV infection. Public Health Service recommended routine hepatitis A vaccination of all children.

Other groups considered being 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. Because of an increased risk of fulminant hepatitis AпїЅobserved in some experiences but not confirmed in othersпїЅamong 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 hepatitis A endemicity.

Recommendations for dose and frequency differ for the two approved vaccine preparations Table ; all injections are IM. Hepatitis A vaccine has been reported to be effective in preventing secondary household and day care centerпїЅassociated cases of acute hepatitis A. Because the vaccine provides long-lasting protection and is simpler to use, in , the Immunization Practices Advisory Committee of the U. Public Health Service favored hepatitis A vaccine to IG for postexposure prophylaxis of healthy persons age 2пїЅ40 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 vaccineпїЅassociated reductions in the annual incidence of new infections. These doses are recommended at months 0, 1, and 6. Until , prevention of hepatitis B was based on passive immunoprophylaxis either with standard immunoglobulin, 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 , was prepared from purified, noninfectious nm spherical HBsAg particles derived from the plasma of healthy HBsAg carriers. In , 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 preexposure and postexposure prophylaxis.

Pregnancy is not a contraindication to vaccination. In areas of low HBV endemicity such as the United States, despite the availability of safe and effective hepatitis B vaccines, a strategy of vaccinating persons in high-risk groups was not effective. Therefore, to have an impact on the frequency of HBV infection in an area of low endemicity such as the United States, universal hepatitis B vaccination in childhood has been recommended. They update the care and treatment section of the WHO Guidelines for the screening, care and treatment of persons with hepatitis C infection issued in April Published on 10 March Modified on 08 May downloads.

Published on 18 April Modified on 08 May downloads. The objective of these guidelines is to provide evidence-based recommendations on screening for, and the care and treatment of, persons with chronic hepatitis C virus HCV infection. They are primarily intended to provide a framework for the development or strengthening of hepatitis C treatment programmes.

Published on 15 July Modified on 06 May downloads. According to recent estimates, more than million people around the world have been infected with the hepatitis C virus HCV , of whom die each year. One third of those who become chronically infected are predicted to develop liver cirrhosis or hepatocellular carcinoma.

Despite the high prevalence of disease, most people infected with the virus are unaware of their infection. Published on 10 May Modified on 10 May downloads. These guidelines outline the public health approach to strengthening and expanding current testing practices for HBV and HCV infection, and are intended for use across age groups and populations. Published on 01 May Modified on 01 May downloads.

Published on 01 May Modified on 06 May downloads. Published on 02 July Modified on 02 May downloads. This document provides guidance for immunization managers and maternal child health partners seeking to introduce hepatitis B birth dose vaccination into their national immunization programmes, placing particular emphasis on the unique programmatic features of birth dose vaccination and the necessary integration with obstetric and post-natal care.

This document will also be helpful for countries that have already introduced HepB-BD but would like to improve coverage.

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Now before that we move on to sharing the free PDF download of Comprehensive Textbook of Hepatitis B PDF with you, here are a few important details regarding this book which you might be interested.

It is very good book to study a day before your exam. It can also cover your viva questions and will help you to score very high. During last 3 decades, significant improvement has been taken place in the fields of epidemiology, virology, diagnosis, pathogenesis, control and management of different infectious diseases.

However, positive developments may not been properly reflected in the clinics in the context of hepatitis B virus HBV. The virus was detected in s, a potent vaccine against the HBV is available from early s, and several antiviral drugs against HBV have been developed during last 3 decades. However, about 50 million new HBV-infected subjects emerge each year, and about 0.

One of the new contributions of this book lies in the fact that in addition to well-accepted concepts about HBV, emerging findings about HBV from ongoing researches have been included in each chapter. Thus, the readers of the book would be able to decide how the information of the laboratory benches may be applied to develop evidence-based control and management strategies against the HBV. These chapters will keep medical students, post graduate students, medical teachers and scientists of different fields of biology updated about HBV in a comprehensive manner.

He has authored more than peer-reviewed publications and is on the editorial board of Infectious Diseases and Therapy. I am planning to start medical school this year. He said they use Netter. So I searched just on Netter and came across this option. I am very pleased with the quality and detail. I am excited like a little kid! I will continue to read through as much material prior to starting school, and I know these will be absolutely invaluable throughout my entire med school journey.

The collection is fine. I personally got volume 9 from a different set. The green books are a phenomenal resource for medicine. The images and information about various diseases have been an invaluable resource in my medical education and practice. Wonderful artworks from Dr. Netter, I admire him from medical students. But the paper is not so good in order to read in the room lightпїЅ.

None of the books or software is hosted on our website. These are only links to external sources. Download file click here. You may send an email to [email protected]. Thursday, February 9, All Things Medicine. Free Medical Books. Share on Facebook. Page Contents.