Figure 58-15. Clinical course of chronic hepatitis D infection.

HEPATITIS E VIRUS

Molecular Structure

Hepatitis E virus (HEV) is a nonenveloped single-stranded RNA virus. It is 30 nm in diameter and is

most similar to other viruses of the Caliciviridae family. There are three large open reading frames, the

first of which is 1,693 codons and codes for nonstructural proteins. The second is 660 codons and

encodes structural proteins. The third is smaller and of undetermined function. There are thought to be

four genotypes.49

Epidemiology/Risk Factors for Transmission

Hepatitis E is enterically transmitted and is epidemiologically similar to HAV. Infection has been

prominently observed in Asia, Africa, the Middle East, and Central America. In addition, vertical

transmission from mother to child has been documented and can be a source of perinatal morbidity and

mortality.

Clinical Features

HEV generally causes a self-limited acute infection, although chronic infection has been described in

organ transplant recipients. The incubation period usually lasts 3 to 8 weeks, and most individuals

recover without chronic findings after a transient cholestatic episode (Fig. 58-16). However, young

adults and women in late stages of pregnancy may develop fulminant cases of hepatitis E. Mortality

from HEV is 0.5% to 4% in the general population but up to 20% in pregnant women.50–52 Diagnosis is

aided by detection of serum or fecal genomes during the acute phase. In addition, one can demonstrate

anti-HEV IgM or IgG in follow-up.

Figure 58-16. Clinical course of chronic hepatitis E infection. (Reproduced with permission from Expert Reviews in Molecular

Medicine: (99)00129—5 h.htm; 6 December 1999.)

Treatment

Infection in most cases is self-limited; however, in immunosuppressed organ transplant patients HEV can

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cause persistent hepatitis and cirrhosis. There are no randomized controlled trials evaluating treatment

options, but there are observational studies that report benefit with ribavirin treatment in organ

transplant recipients.53

CYTOMEGALOVIRUS

Cytomegalovirus (CMV) is a member of the Beta-Herpesviridae family. It is usually associated with mild

hepatitis but may occasionally cause ALF. Transmission can be intrauterine, perinatal, or postnatal;

through intimate contact of infected fluids such as blood, saliva, or urine, or through transplanted

organs. Infection is lifelong due to the latency of the virus and can be detected in up to 70% of

individuals in US cities. Organ injury can occur as a result of primary infection or due to reactivation of

latent infection. In the neonatal period congenital infection can be severe and fatal. In

immunocompetent adults liver dysfunction tends to be found in association with CMV mononucleosis. In

immunosuppressed adults, infection leads to liver dysfunction with jaundice and at times liver failure.

Acalculous cholecystitis is another presentation.31,54,55 CMV antigenemia and PCR to detect CMV DNA

have made diagnosis rapid. Liver biopsy is important to establish the diagnosis of hepatitis. Pathologic

examination shows inflammation and injury ranging from fatty changes to necrosis to fibrosis. Giant

multinucleated cells and large nuclear inclusions can be encountered in hepatocytes and bile duct

epithelial cells.31,54,55

First-line treatment is with ganciclovir or valganciclovir. Second-line agents for cases of resistant

CMV include foscarnet, or cidofovir. Anti-CMV immune globulin can be used as an adjunct.56

EPSTEIN–BARR VIRUS

Epstein–Barr virus (EBV) is a DNA virus and member of the Herpesviridae family. Infection persists for

life due to latency of the virus and it is usually transmitted by close personal or intimate contact via oral

secretions. Some degree of liver involvement is encountered in almost all cases of primary EBV also

known as mononucleosis. It is usually mild without major clinical manifestations and resolves

spontaneously. The presence of jaundice may reflect either more severe hepatitis or an associated

hemolytic anemia. Occasional cases of ALF have been reported in both the immunocompetent and

immunocompromised population. Leukocytosis is usually present, with the presence of atypical

lymphocytes being a hallmark. Detection of heterophile antibodies, or the “monospot test” is highly

specific but somewhat insensitive with false-negative rates as high as 25% early in infection. If acute

EBV is suspected and heterophile antibodies are not detected EBV-specific antibody testing can be used

which are highly sensitive and specific. Treatment is supportive. Acyclovir has activity against EBV but

clinical trials have not shown a clear benefit to use of acyclovir. Liver transplant has been reported in

rare life-threatening situations.54,56–58

HERPES SIMPLEX VIRUS

The prevalence of antibodies to HSV-1 is around 75% in most populations and around 20% to HSV-2.

Fulminant hepatitis is a rare complication of HSV infection; those at risk include the neonates, the

immunocompromised, the malnourished, and the pregnant adults. Fulminant hepatitis is usually

associated with multiorgan failure and is associated with a high mortality rate. Clinical features include

high fever, anorexia with nausea, abdominal pain, leucopenia, and coagulopathy. Liver biopsy is

important in establishing the diagnosis. Microscopic examination shows diffuse eosinophilic intranuclear

inclusion bodies, multinucleated cells, widespread necrosis, and inflammation. Cowdry A-type

intranuclear inclusions are typical. Confirmation is by PCR. Approved antivirals include acyclovir,

famciclovir, and valacyclovir. Treatment with intravenous acyclovir should be initiated prior to

confirmation of etiology given that progression of disease is extremely rapid and lethal. Liver

transplantation can be considered even in cases of disseminated disease.54–56

VARICELLA ZOSTER VIRUS

Herpesvirus varicella (also called varicella zoster virus [VZV]) is usually associated with mild hepatitis

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but may occasionally cause ALF. Up to one-fourth of children with varicella (chickenpox) may exhibit

temporary mild biochemical liver abnormalities. Reye syndrome may be encountered during the

convalescence period especially in those who receive aspirin. In such cases mortality can be as high as

30%. Fulminant fatal hepatic failure is uncommon, but generally affects immunocompromised patients.

Confirmation of the diagnosis can be achieved by isolation of the virus from affected tissues. Varicella

zoster immune globin should be considered after exposure to the virus in immunocompromised or

pregnant patients who lack immunity to VZV. Current therapies for VZV infection in immunocompetent

and immunocompromised hosts include acyclovir, valacyclovir, and famciclovir. CDC guidelines should

be followed for infection control.31,54,56

ACUTE LIVER FAILURE

Definition

ALF is an uncommon but serious condition with approximately 2,000 cases per year in the United

States

59 and which carries a high mortality rate of 60% to 80%.60 It is characterized by rapid

deterioration of liver function as well as development of hepatic encephalopathy in an individual with

no previous liver disease. Currently, emergency liver transplantation is the only therapeutic option

available, and the King’s College Criteria are widely accepted as the standard of guidance. ALF is

responsible for about 5% of all liver related deaths and approximately 5% of all liver transplants are

performed for this indication.61

The most widely accepted definition includes an international normalized ratio (INR) greater than 1.5

and any degree of mental alteration (encephalopathy) in a patient without pre-existing liver disease and

with an illness of less than 26 weeks’ duration. Patients with Wilson disease, vertically acquired

hepatitis B, or autoimmune hepatitis can be considered to have ALF if the disease process has started

within 26 weeks.62 Although the literature suggests hyperacute (<7 days) and subacute (>21 days but

<26 weeks) forms, they do not have prognostic significance except in the case of hyperacute failure

due to acetaminophen toxicity which may carry a better prognosis.63

Diagnosis

A high index of suspicion is vital in early recognition of the disease process. Patients with evidence of

moderate to severe hepatitis and any degree of encephalopathy require hospitalization since the process

may proceed to death rapidly.64 Likewise early transfer to an intensive care unit (ICU) setting in a liver

transplant center is important (especially before the onset of grade III or IV encephalopathy) since

worsening encephalopathy can potentially hamper transportation efforts due to concerns over increased

intracranial pressure (ICP). Detailed history taking from accompanying persons including medications

and herbal supplements taken and recent social history is essential. Stigmata of chronic liver disease

should be assayed during the physical examination although jaundice may be a relatively late

manifestation of the disease process. The initial recommended laboratory testing is listed in Table 58-

2.64 Lastly, transjugular liver biopsy can be considered as part of the initial workup to rule out

neoplastic infiltration or HSV/herpes zoster virus (HZV) infection, although it is not always necessary,

beneficial, or safe in all cases.63

Table 58-2 Management in Acute Liver Failure: Initial Laboratory Evaluations

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Etiology

Etiology is important in ALF in that it may dictate administration of appropriate antidotes or to better

anticipate prognosis and the potential need for liver transplantation.65 Etiology seems to have

geographic variation. In the United States, the most common reported cause of ALF is acetaminophen

overdose (45% of cases), followed by unknown (15%), drug related (10%), hepatitis B virus (7%),

autoimmune hepatitis (5%), and Wilson disease (2%).66 In the United Kingdom, acetaminophen toxicity

is reported in over 60% of cases, whereas in France, frequency of reported etiologies is viral due to

hepatitis A and B (30%), acetaminophen (20%), other drug over dose (18%), and unknown (17%).63,67

Drug-induced Liver injury. Intrinsic hepatotoxins are usually dose dependent, while idiosyncratic

responses are dose independent. Acetaminophen toxicity is dose dependent with serious injury seen with

levels greater than 10 g/day but sometimes reported in cases with levels as low as 3 to 4 g/day range.

Glutathione becomes depleted with excess free NAPQI (a toxic byproduct of acetaminophen) reacting

with hepatocytes, causing liver injury.65 In the presence of poor nutritional state or alcoholism,

glutathione levels are chronically depleted further contributing to toxicity. Stevens–Johnson syndrome

caused by phenytoin, amoxicillin-clavulanate, carbamazepine, or halothane, is a form of hypersensitivity

idiosyncratic reaction, while isoniazid, valproate, and amiodarone mainly cause metabolic idiosyncratic

reactions.

Viral Hepatitis. In those with HAV, ALF occurs around 0.5% of the time; age over 40 and other preexisting liver disease represent increased risk. In those with HBV, ALF occurs in 1.5% of cases. ALF may

occur due to new infection or reactivation of a chronic carrier state. HDV coinfection and HEV should be

suspected in endemic areas. VZV, HSV, and CMV are other rare viral causes of ALF.65

Other. Acute Budd–Chiari syndrome, veno-occlusive disease, medications and herbs, and

malignancies involving the liver (i.e., lymphoma, angiosarcoma) are less common causes of ALF.64

Acute fatty liver of pregnancy (AFLP), and HELLP (Hemolysis, Elevated liver enzymes, Low platelets)

are important diagnoses to be considered among pregnant women presenting with manifestations of

ALF. AFLP occurs during the third trimester of pregnancy due to deficiencies in 3-hydroxyacyl-CoA

dehydrogenase in both the mother and fetus with rapid deposition of triglycerides and free fatty acids

into hepatocytes. HELLP also occurs in the third trimester or immediately postpartum. Autoimmune

hepatitis (AIH) can present acutely with absence of autoimmune markers, where the diagnosis is made

by exclusion and transjugular liver biopsy. In the fulminant form of Wilson disease, chelator treatment

is ineffective and diagnosis is usually based on familial history of liver disease in a young adult with

Coombs-negative hemolysis and low serum alkaline phosphatase or uric acid levels. Kayser–Fleischer

rings are present in 50% of patients.62 Diagnosis is usually confirmed by hepatic copper content greater

than 250 μg/g in patients homozygous for Wilson disease, and the rate of urinary excretion may exceed

100 μg/24 hours.68 Heat stroke, mushroom ingestion, EBV, and parvovirus B19 are rare causes of ALF.63

Clinical Features, Management, and Treatment

Acute liver injury in the absence of hepatic encephalopathy is a reversible entity unless an underlying

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