2576 PART 10 Disorders of the Gastrointestinal System

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).

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

anti-HBc-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.

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 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. When such antibody

is detected, its presence is of no recognized clinical significance (see

“Virology and Etiology”).

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 339-5. 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

sensitivity, 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. 341).

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 decompensation, and

hepatocellular carcinoma (see “Complications and Sequelae”).

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 (which is 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 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.

Amplification techniques are required to detect HCV RNA. Currently, such target amplification (i.e., synthesis of multiple copies of the viral genome) is achieved by PCR, in which the viral

RNA is reverse transcribed to complementary DNA and then amplified by repeated

cycles of DNA synthesis. Quantitative PCR

assays provide a measurement of relative

“viral load”; current PCR assays have a

sensitivity of 10 (lower limit of detection)

to 25 (lower limit of quantitation) IU/mL

and a wide dynamic range (10–107

 IU/mL).

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. 341). 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. 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

TABLE 339-5 Commonly Encountered Serologic Patterns of Hepatitis B Infection

HBsAg ANTI-HBs ANTI-HBc HBeAg ANTI-HBe INTERPRETATION

+ − IgM + − Acute hepatitis B, high infectivitya

+ − IgG + − Chronic hepatitis B, high infectivity

+ − IgG − + 1. Late acute or chronic hepatitis B, low

infectivity

2. HBeAg-negative (“precore-mutant”)

hepatitis B (chronic or, rarely, acute)

+ + + +/− +/− 1. HBsAg of one subtype and heterotypic

anti-HBs (common)

2. Process of seroconversion from HBsAg to

anti-HBs (rare)

− − IgM +/− +/− 1. Acute hepatitis Ba

2. Anti-HBc “window”

− − IgG − +/− 1. Low-level hepatitis B carrier

2. Hepatitis B in remote past

− + IgG − +/− Recovery from hepatitis B

− + − − − 1. Immunization with HBsAg (after vaccination)

2. Hepatitis B in the remote past (?)

3. False-positive

a

IgM anti-HBc may reappear during acute reactivation of chronic hepatitis B.

Note: See text for abbreviations.

2577Acute Viral Hepatitis CHAPTER 339

current HBV infection with low-level virus carriage. Detectable antiHCV in the absence of HCV RNA signifies spontaneous or therapeutically induced recovery from (“cured”) hepatitis C.

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 antiHDV). 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.

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. 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.

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 outside the United States; in the

United States, although tests for HEV infection are not approved by the

FDA, reliable diagnostic serologic/virologic assays can be performed at

the CDC or other commercial or academic 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.

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 339-6). 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

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 (no other proven

human hepatitis viruses have been identified), if the epidemiologic

setting is appropriate.

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. 341). 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.

■ PROGNOSIS

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 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 (but only very rarely or not at all in

nonendemic 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 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

(“Lábrea fever”), a mortality rate >20% has

been recorded.

■ COMPLICATIONS AND

SEQUELAE

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

TABLE 339-6 Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis

SEROLOGIC TESTS OF PATIENT’S SERUM

HBsAg DIAGNOSTIC INTERPRETATION 

IgM

ANTI-HAV

IgM

ANTI-HBc ANTI-HCV

+ − + − Acute hepatitis B

+ − − − Chronic hepatitis B

+ + − − Acute hepatitis A superimposed on chronic hepatitis B

+ + + − Acute hepatitis A and B

− + − − Acute hepatitis A

− + + − Acute hepatitis A and B (HBsAg below detection

threshold)

− − + − Acute hepatitis B (HBsAg below detection threshold)

− − − + Acute hepatitis C

Note: See text for abbreviations.

2578 PART 10 Disorders of the Gastrointestinal System

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. 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 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. 108). 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. 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. 341). Finally, chronic hepatitis C has been linked to multiple

extrahepatic disorders, including cardiovascular and cerebrovascular

disease, renal disease, rheumatologic/immunologic disorders, mental

health and cognitive disorders (many patients describe “brain fog”),

and, in addition to hepatocellular carcinoma, nonliver malignancies.

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 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 lifesaving in patients with fulminant

hepatitis (Chap. 345).

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 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.

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. 341).

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.

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 and accelerate

the risk of hepatocellular carcinoma. Some HDV superinfections in

patients with chronic hepatitis B lead to fulminant hepatitis. As defined

in longitudinal studies over three decades, the annual rate of cirrhosis

in patients with chronic hepatitis D is 4%. 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.

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. Among cirrhotic patients

with chronic hepatitis C, the annual risk of hepatic decompensation

is ~4%. Although prior to the availability of highly effective DAA

therapy during the second decade of the twenty-first century chronic

hepatitis C accounted 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 severe and rapidly progressive chronic hepatitis B and C are being recognized with increasing

frequency in patients with HIV infection (Chap. 202). 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 and even hepatocellular carcinoma) have been

observed in immunosuppressed organ-transplant recipients, persons

receiving cytotoxic chemotherapy, and persons with HIV infection.

Among patients with chronic hepatitis (e.g., caused by hepatitis B or C,

alcohol, etc.) in endemic countries, hepatitis E has been reported as the

cause of acute-on-chronic liver failure; however, in most experiences

among patients from nonendemic countries, HEV has not been found

to contribute commonly to hepatic decompensation in patients with

chronic hepatitis.

Persons with chronic hepatitis B, particularly those infected in

infancy or early childhood and especially those with HBeAg and/or

2579Acute Viral Hepatitis CHAPTER 339

high-level HBV DNA, have an enhanced risk of hepatocellular carcinoma. The risks of cirrhosis and hepatocellular carcinoma increase

with the level of HBV replication. The annual rate of hepatocellular

carcinoma in patients with chronic hepatitis D and cirrhosis is ~3%.

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. 82). Among such cirrhotic patients with

chronic hepatitis C, the annual risk of hepatocellular carcinoma is

~1–4%.

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. 341) can be triggered by a

bout of otherwise self-limited acute hepatitis, as reported after acute

hepatitis A, B, and C.

■ DIFFERENTIAL DIAGNOSIS

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, including the coronavirus SARS-CoV-2 (~10% of all

cases and up to half of severe cases); 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. 340). Equally important is a history of unexplained “repeated

episodes” of acute hepatitis. This history should alert the physician

to the possibility that the underlying disorder is chronic hepatitis, for

example, autoimmune hepatitis (Chap. 341). 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 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 veno-occlusive 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 (hemolysis, elevated liver tests, and low platelets) 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. Among patients with

biochemical evidence for severe liver injury, i.e., aminotransferase levels of ≥1000 IU/L, the most common causes are ischemic liver injury,

drug-induced liver injury (especially caused by acetaminophen), acute

viral hepatitis, and pancreaticobiliary disorders.

TREATMENT

Acute Viral Hepatitis

Most persons with acute hepatitis (especially hepatitis A, B, and E)

recover spontaneously and do not require specific antiviral therapy.

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. 341) 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.

In typical cases of acute hepatitis C, recovery is rare (~15–20%

in most experiences), and progression to chronic hepatitis is the

rule. Patients with jaundice, those with HCV genotype 1, women,

and those with earlier age of infection, lower level of HCV RNA,

HBV co-infection, and absence of current injection drug use are

more likely to recover from acute hepatitis C, as are persons who

have genetic markers associated with spontaneous recovery (IL28B

CC haplotype).

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 3–6 months (after

which recovery is unlikely) was a recommended approach during

the era of interferon-based therapy; however, in the current era of

highly effective (95–100%) oral DAA therapy, waiting for potential

spontaneous recovery is no longer advised; instead, early treatment

with one of the four first-line drug combinations (of polymerase

inhibitors, protease inhibitors, and/or NS5A inhibitors) approved

for treatment of chronic hepatitis C (Chap. 341) is recommended

for treatment of patients with acute hepatitis C. Although abbreviated treatment courses have been studied, currently, a standard, full

8- to 12-week course is recommended.

Because of the vast reservoir of acute HCV infections acquired

four to five decades ago in the 1945–1965 birth cohort, most newly

recognized HCV infections are chronic. Opportunities to identify and

treat patients with acute hepatitis C occur in two population subsets:

(1) in health care workers who sustain hepatitis C–contaminated

needle sticks (occupational accidents), monitoring for ALT elevations and the presence of HCV RNA identify acute hepatitis C in

~3%, and this group should be treated; (2) in injection drug users,

the risk of acute hepatitis C has been on the rise during the previous decade, and the epidemic of opioid use has contributed to an

amplification of HCV infection among drug users. 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

2580 PART 10 Disorders of the Gastrointestinal System

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.g., of acute hepatitis B).

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.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.

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. 345). Fulminant hepatitis C is very rare; however, in

fulminant hepatitis B, oral antiviral therapy has been used successfully,

as reported anecdotally. In clinically severe acute hepatitis E or acuteon-chronic liver failure, successful therapy with ribavirin (600 mg

twice daily, 15 mg/kg) has been reported anecdotally. Unfortunately,

when fulminant hepatitis E occurs in pregnant women (as it does in up

to 20% of pregnant women with acute hepatitis E), ribavirin, which is

teratogenic, is contraindicated. In cases of hepatitis E in organ-transplant

recipients, reduction in overall immunosuppressive drug doses and

switching from tacrolimus to cyclosporine A have been shown to be

effective, often without antiviral therapy, in achieving eradication of

HEV. If a change in immunosuppression is inadequate, ribavirin treatment for 3 months has been observed to achieve a sustained virologic

response in 78% of treated patients; however, the optimal dose and

duration of ribavirin therapy remain to be determined.

■ PROPHYLAXIS

Because application of therapy for acute viral hepatitis is limited and

because chronic viral hepatitis requires prolonged and costly courses

of antiviral therapy (Chap. 341), 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.

Hepatitis A Both passive immunization with immunoglobulin (IG)

and active immunization with killed vaccines are available. All preparations of IG contain anti-HAV concentrations sufficient to be protective.

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 been associated with transmission of HBV, HCV, or HIV.

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. By the time most commonsource outbreaks of hepatitis A are recognized, it is usually too late in

the incubation period for IG to be effective; however, prophylaxis may

have limited 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.

Such IG recommendations for postexposure prophylaxis and for

preexposure prophylaxis for international travel were updated in

2018. Currently, hepatitis A vaccine, not IG, is recommended for

all persons aged ≥12 months for postexposure prophylaxis and for

preexposure prophylaxis prior to international travel to HAV-endemic areas. For adults aged >40, IG (at an upward revised dose

of 0.1 mg/kg) may be added to postexposure hepatitis B vaccination depending on an assessment of the person’s risk. Even though

hepatitis A vaccine is indicated for children ≥12 months of age, when

infants aged 6–11 months travel internationally to areas with a risk

of HAV infection, they should receive the vaccine for preexposure

prophylaxis; however, this travel-related dose should not be counted

toward the universal childhood two-dose hepatitis A vaccine recommendation, which begins at age 12 months. For postexposure prophylaxis of persons with contraindications to hepatitis A vaccination

and infants aged <12 months, the use of IG (0.1 mL/kg) should be

retained. In addition, for postexposure prophylaxis in immunocompromised adults and persons with chronic liver disease, both hepatitis

A vaccination and IG administration (0.1 mL/kg), at different IM

sites, are recommended. Finally, for infants aged <6 months and for

persons with contraindications to hepatitis A vaccination, preexposure prophylaxis for travel consists of IG at doses of 0.1 mg/kg for

travel durations up to 1 month, 0.2 mg/kg for travel up to 2 months,

and repeat 0.2 mg/kg every 2 months thereafter for the remainder

of travel. Thus, except for these limited considerations, hepatitis A

vaccine has supplanted IG in almost all cases for both postexposure prophylaxis and preexposure prophylaxis for travel. Unlike IG

prophylaxis, the protection afforded by active immunization with

vaccine is durable and simpler to administer.

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. As

noted above, for travel to an endemic area, hepatitis A vaccine is the

preferred approach to preexposure immunoprophylaxis and provides

long-lasting protection (protective levels of anti-HAV should last at

least 20 years after vaccination). 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

2581Acute Viral Hepatitis CHAPTER 339

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 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.g., Alaskan natives), employees of day-care centers and persons working in

facilities for the developmentally delayed, primate handlers, laboratory

workers exposed to hepatitis A or fecal specimens, and patients with

chronic liver disease (including persons with aminotransferase elevations ≥2 times the upper limit of normal). 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 and the expanding population of

persons with nonalcoholic liver disease. Other populations whose recognized risk of hepatitis A is increased should be vaccinated, including

men who have sex with men, injection or noninjection drug users,

persons experiencing homelessness, 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. Hepatitis A vaccine is now

recommended as well for pregnant women at risk of infection or severe

outcomes from infection during pregnancy. Recommendations for

dose and frequency differ for the two approved vaccine preparations in

the United States and the combination vaccines that include hepatitis

A (Table 339-7); all injections are IM. Hepatitis A vaccine has been

reported to be effective in preventing secondary household and daycare center–associated cases of acute hepatitis A. 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.

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 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 were licensed for use in the United States in the 1980s

(Recombivax-HB 1986; Engerix-B 1989), and a third (Heplisav-B)

was licensed in 2017. Current recommendations can be divided into

those for preexposure and postexposure prophylaxis.

For preexposure prophylaxis against hepatitis B in settings of frequent exposure (health workers exposed to blood; first-responder public safety workers; hemodialysis patients and staff; residents and staff of

custodial institutions for the developmentally handicapped; injection

drug users; incarcerated inmates of correctional facilities; persons

with multiple sexual partners or who have had a sexually transmitted

disease; men who have sex with men; persons such as hemophiliacs

who require long-term, high-volume therapy with blood derivatives;

household and sexual contacts of persons with chronic HBV infection;

persons living in or traveling extensively in endemic areas; unvaccinated children aged <18; unvaccinated children who are Alaskan

natives, Pacific Islanders, or residents in households of first-generation

immigrants from endemic countries; persons born in countries with a

prevalence of HBV infection ≥2%; patients with chronic liver disease

[including persons with aminotransferase levels >2 times the upper

limit of normal]; persons aged <60 years with diabetes mellitus [those

≥60 years at the discretion of their physicians]; persons with end-stage

renal disease; and persons with HIV infection), three IM (deltoid, not

gluteal) injections of hepatitis B vaccine are recommended at 0, 1, and

6 months (other, optional schedules are summarized in Table 339-8).

Pregnancy is not a contraindication to vaccination (but Heplisav-B

is not recommended for pregnant women because of the lack of

safety data in this subpopulation; details of the use of Heplisav-B, a

two-injection course a month apart, appear in Table 339-8). 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. The incidence of new

hepatitis B cases continued to increase in the United States after the

introduction of vaccines; <10% of all targeted persons in high-risk

groups were actually vaccinated, and ~30% of persons with sporadic

acute hepatitis B did not fall into any high-risk group category. 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 is recommended. For unvaccinated children born

after the implementation of universal infant vaccination, vaccination

during early adolescence, at age 11–12 years, is recommended, and

this recommendation has been extended to include all unvaccinated

children aged 0–19 years. In HBV-hyperendemic areas (e.g., Asia),

universal vaccination of children has resulted in a marked (~70–90%)

30-year decline in complications of hepatitis B, including liver-related

mortality and hepatocellular carcinoma.

The original two available aluminum-adjuvanted recombinant hepatitis B vaccines are comparable, one containing 10 μg of

HBsAg (Recombivax-HB) and the other containing 20 μg of HBsAg

(Engerix-B), and recommended doses for each injection vary for the

two preparations (Table 339-8). Combinations of hepatitis B vaccine

with other childhood vaccines are available as well (Table 339-8).

In 2017, a third recombinant hepatitis B vaccine with a novel adjuvant that activates Toll-like 9 receptors was approved for adults aged 18

or older. In a series of prospective trials, compared to three Engerix-B

injections, two IM doses a month apart yielded higher proportions with

protective levels of anti-HBs (≥10 mIU/mL): 95% of adults aged 18–55

or 18–70 (vs 81% for Engerix-B), 90% of older adults aged 40–70 (vs

71% for Engerix-B), and 90% of adults aged 18–70 with type 2 diabetes

(vs 65% for Engerix-B). This two-injection regimen may be useful for

revaccination of persons who failed to respond to the original vaccines.

Another novel recombinant vaccine (PreHevbrio, VBI Vaccines) containing of all three hepatitis B surface antigens, S, pre-S1, and pre-S2,

has been shown in clinical trials (three IM doses at 0, 1, and 6 months)

to achieve higher proportions with protective anti-HBs and higher

antibody levels than Engerix-B (which contains S antigen only), including in older persons (≥45 years), persons with diabetes, and overweight

persons (body mass index >30); approved originally outside the United

States, this vaccine was approved by the FDA on December 1, 2021 for

adults age ≥18 years. Availability is expected during the first quarter

of 2022.

TABLE 339-7 Hepatitis A Vaccination Schedules

AGE, YEARS NO. OF DOSES DOSE

SCHEDULE,

MONTHS

HAVRIX (GlaxoSmithKline)a

1–18

≥19

2

2

720 ELUb

 (0.5 mL)

1440 ELU (1 mL)

0, 6–12

0, 6–12

VAQTA (Merck)

1–18

≥19

2

2

25 units (0.5 mL)

50 units (1 mL)

0, 6–18

0, 6–18

a

A 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.

b

Enzyme-linked immunoassay units. c

Combination hepatitis A and typhoid vaccines,

Hepatyrix (GlaxoSmithKline) and Viatim (Sanofi Pasteur), are available, targeted

primarily for travelers to endemic areas. Please consult product insert for doses

and schedules

2582 PART 10 Disorders of the Gastrointestinal System

For unvaccinated persons sustaining an exposure to HBV, postexposure prophylaxis with a combination of HBIG (for rapid achievement

of high-titer circulating anti-HBs) and hepatitis B vaccine (for achievement of long-lasting immunity as well as its apparent efficacy in attenuating clinical illness after exposure) is recommended. For perinatal

exposure of infants born to HBsAg-positive mothers, a single dose of

HBIG, 0.5 mL, should be administered IM in the thigh immediately

after birth, followed by a complete course of three injections of recombinant hepatitis B vaccines approved for children (see doses above) to

be started within the first 12 h of life. For those experiencing a direct

percutaneous inoculation or transmucosal exposure to HBsAg-positive blood or body fluids (e.g., accidental needle stick, other mucosal

penetration, or ingestion), a single IM dose of HBIG, 0.06 mL/kg,

administered as soon after exposure as possible, is followed by a complete course of hepatitis B vaccine to begin within the first week. For

pregnant mothers with high-level HBV DNA (>2 × 105

 IU/mL), adding

antiviral nucleoside analogues (e.g., pregnancy class B tenofovir, see

Chap 341) during the third trimester of pregnancy reduces perinatal

transmission even further. For persons exposed by sexual contact to a

patient with acute hepatitis B, a single IM dose of HBIG, 0.06 mL/kg,

should be given within 14 days of exposure, to be followed by a complete course of hepatitis B vaccine. When both HBIG and hepatitis B

vaccine are recommended, they may be given at the same time but at

separate sites. Testing adults for anti-HBs after a course of vaccine is

advisable to document the acquisition of immunity, but because hepatitis B vaccine immunogenicity is nearly universal in infants, postvaccination anti-HBs testing of children is not recommended.

The precise duration of protection afforded by hepatitis B vaccine is unknown; however, ~80–90% of immunocompetent adult

vaccinees retain protective levels of anti-HBs for at least 5 years, and

60–80% for 10 years, and protective antibody has been documented

to last for at least two decades after vaccination in infancy. Thereafter

and even after anti-HBs becomes undetectable, protection persists

TABLE 339-8 Preexposure Hepatitis B Vaccination Schedules

TARGET GROUP NO. OF DOSES DOSE SCHEDULE, MONTHS

Recombivax-HB (Merck)a

Infants, children (<1–10 years)

Adolescents (11–19 years)

Adults (≥20 years)

Hemodialysis patientsb

<20 years

≥20 years

3

3 or 4

or

2

3

3

3

5 μg (0.5 mL)

5 μg (0.5 mL)

10 μg (1 mL)

10 μg (1 mL)

5 μg (0.5 mL)

40 μg (4 mL)

0, 1–2, 4–6

0–2, 1–4, 4–6 or 0, 12, 24 or 0, 1, 2, 12

0, 4–6 (age 11–15)

0–2, 1–4, 4–6

0, 1, 6

0, 1, 6

Engerix-B (GlaxoSmithKline)c

Infants, children (<1–10 years)

Adolescents (10–19 years)

Adults (≥20 years)

Hemodialysis patientsb

<20 years

≥20 years

3 or 4

3 or 4

3 or 4

4

4

10 μg (0.5 mL)

10 μg (0.5 mL)

20 μg (1 mL)

10 μg (0.5 mL)

40 μg (2 mL)

0, 1–2, 4–6 or 0, 1, 2, 12

0, 1–2, 4–6 or 0, 12, 24 or 0, 1, 2, 12

0–2, 1–4, 4–6 or 0, 1, 2, 12

0, 1, 2, 6

0, 1, 2, 6

Heplisav-B (Dynavax)d

Adults (≥18 years) 2 20 μg (0.5 mL) 0, 1

a

This manufacturer produces a licensed combination of hepatitis B vaccine and vaccines against Haemophilus

influenzae type b and Neisseria meningitides, Comvax, for use in infants and young children. Please consult

product insert for dose and schedule. b

This group also includes other immunocompromised persons. c

This

manufacturer produces two licensed combination hepatitis B vaccines: (1) Twinrix, recombinant hepatitis B

vaccine plus inactivated hepatitis A vaccine, is licensed for simultaneous protection against both of these

viruses among adults (age ≥18 years). Each 1-mL dose contains 720 ELU (enzyme-linked immunoassay units) of

hepatitis A vaccine and 20 μg of hepatitis B vaccine. These doses are recommended at months 0, 1, and 6. (2)

Pediarix, recombinant hepatitis B vaccine plus diphtheria and tetanus toxoid, pertussis, and inactivated poliovirus,

is licensed for use in infants and young children. A hexavalent vaccine combining diphtheria, tetanus toxoid,

pertussis, poliovirus, H. influenzae type b, and hepatitis B (Vaxelis, MCM Vaccine Company) was approved by the

U.S. Food and Drug Administration in 2018. Please consult product insert for doses and schedules. d

Heplisav-B

has not been tested for safety and efficacy in children, adolescents, hemodialysis patients, and pregnant women;

it is not approved for these subpopulations.

against clinical hepatitis B, hepatitis B surface

antigenemia, and chronic HBV infection.

Currently, booster immunizations are not

recommended routinely, except in immunosuppressed persons who have lost detectable anti-HBs or immunocompetent persons

who sustain percutaneous HBsAg-positive

inoculations after losing detectable antibody.

Specifically, for hemodialysis patients, annual

anti-HBs testing is recommended after vaccination; booster doses are recommended

when anti-HBs levels fall to <10 mIU/mL. As

noted above, for persons at risk of both hepatitis A and B, a combined vaccine is available

containing 720 enzyme-linked immunoassay

units (ELUs) of inactivated HAV and 20 μg of

recombinant HBsAg (at 0, 1, and 6 months).

Hepatitis D Infection with hepatitis D

can be prevented by vaccinating susceptible

persons with hepatitis B vaccine. No product is available for immunoprophylaxis to

prevent HDV superinfection in persons with

chronic HBV infection; for these patients,

avoidance of percutaneous exposures and

limitation of intimate contact with persons

who have HDV infection are recommended.

Hepatitis C IG is ineffective in preventing hepatitis C and is no longer recommended for postexposure prophylaxis in

cases of perinatal, needle stick, or sexual

exposure. Although prototype vaccines that

induce antibodies to HCV envelope proteins

have been developed, currently, hepatitis C

vaccination is not feasible practically. Genotype and quasispecies viral heterogeneity, as well as rapid evasion of

neutralizing antibodies by this rapidly mutating virus, conspire to

render HCV a difficult target for immunoprophylaxis with a vaccine.

Prevention of transfusion-associated hepatitis C has been accomplished by the following successively introduced measures: exclusion

of commercial blood donors and reliance on a volunteer blood supply;

screening donor blood with surrogate markers such as ALT (no longer

recommended) and anti-HBc, markers that identify segments of the

blood donor population with an increased risk of bloodborne infections; exclusion of blood donors in high-risk groups for AIDS and the

introduction of anti-HIV screening tests; and progressively sensitive

serologic and virologic screening tests for HCV infection.

In the absence of active or passive immunization, prevention of

hepatitis C includes behavior changes and precautions to limit exposures to infected persons. Recommendations designed to identify

patients with clinically inapparent hepatitis as candidates for medical

management have as a secondary benefit the identification of persons

whose contacts could be at risk of becoming infected. A so-called lookback program has been recommended to identify persons who were

transfused before 1992 with blood from a donor found subsequently

to have hepatitis C. In addition, anti-HCV testing, once recommended

for persons born between 1945 and 1965, has now been expanded to

include all persons 18 year or older, independent of risk factors. Groups

at higher risk and for whom testing is recommended include anyone

who received a blood transfusion or a transplanted organ before the

introduction of second-generation screening tests in 1992, those who

ever used injection drugs (or took other illicit drugs by noninjection

routes), chronically hemodialyzed patients, persons with clotting disorders who received clotting factors made before 1987 from pooled

blood products, persons with elevated aminotransferase levels, health

workers exposed to HCV-positive blood or contaminated needles,

recipients of blood or organs from a donor found to be positive for

hepatitis C, persons with HIV infection, health care and public safety