Worldwide, approximately 1.5 million clinical cases of hepatitis A occur annually but the rate of infection is likely ten times higher. The incidence rate is strongly related to economics and access to clean drinking water: as mean-income rises and access to clean water improves, the incidence of hepatitis A infection decreases [2].

Distribution of hepatitis A infection worldwide is classified as areas of high, intermediate or low endemicity (see Fig. 9.2) [1, 2]. These areas are differentiated by standards of hygiene and sanitation, the age-dependent clinical expression of the disease, and lifelong immunity [3]. In highly endemic areas of the world, poor sanitation and hygiene lead to most persons being infected at a very young age, when the disease usually has no symptoms. These areas include most of Africa, Asia, and Central/South America.

In developing countries, such as Eastern Europe and other parts of Africa, Asia, and America, sanitation and hygiene is variable [2]. This allows many children to avoid infection in early childhood. Peak incidence in these countries is often in later childhood and adolescents. Infection is later childhood is associated with higher rate of symptomatology. Outbreaks in these countries are often associated with person-to-person contact and are harder to control with standard hygiene measures [2].

In more developed countries, such as North America, Western Europe, Australia, and Japan, sanitation and hygiene is better. This leads to a low incidence and infection rate of hepatitis A. Outbreaks in these countries are often seen with large person-to-person outbreaks (often single source outbreaks such as infected food handler or a contaminated food source from an endemic country) or in specific adult risk groups such as travelers to endemic areas, persons who use intravenous drugs or men who have sex with men [2].

In contrast to hepatitis A, hepatitis E is not a reportable disease to the CDC in the USA, so less is known about the exact incidence. Worldwide, it is estimated that one-third of the population has been infected, although the actual disease burden is unknown [4]. Similarly to hepatitis A, hepatitis E has a distinct epidemiological pattern that is based on different rates of infection (see Fig. 9.3] [4]. These areas not only differ in numbers but in routes of transmission, affected persons, and disease characteristics [5].

B. Transmission of hepatitis A and E

How are hepatitis A and E spread?

B.1 Routes of transmission

B.2 Hosts (humans, animals), infectivity period, incubation period

B.3 Sporadic versus epidemic forms

In general, hepatitis A and E are both spread through similar routes. They are both enteric pathogens and are spread through fecal–oral route. Most commonly this is through ingestion of contaminated drinking water. This is where the similarities end, as hepatitis E has the ability to take other routes of infectivity, including different hosts [6, 7].

The incubation period of hepatitis A is roughly 28 days (range of 15–50 days).

Hepatitis A, after infection, replicates in the liver [1]. Humans are the only host for hepatitis A. During the initial period of infectivity (10–12 days), the virus is present in blood and excreted via the biliary system into the feces. It reaches peak titers about 2 weeks before the onset of symptoms. As viral replication and excretion begins to wane, symptoms begin to appear. These symptoms are often indistinguishable from other viral hepatitis’. They include a sudden onset of fever, fatigue, anorexia, nausea, abdominal discomfort, dark urine, and jaundice. Viral excretion has significantly decreased by 7–10 days after the onset of symptoms, with most infected patients no longer shedding virus in the feces by the third week of illness [7, 8].

The clinical illness associated with hepatitis A does not usually last greater than 2 months, but can develop a prolonged or relapsing state in 10–15 % of patients [1]. This can last up to 6 months, with virus being excreted during these relapses [1].

Hepatitis E can have different modes of transmission and reservoirs based on endemic locations worldwide [5]. In areas of the world that are highly endemic, such as Asia, Africa, and Central America, infection is most often transmitted through the fecal–oral route with contaminated drinking water. Water contamination is often related to heavy rainfall and floods. This can lead to large outbreaks of the disease, often affecting thousands of individuals. One to fifteen percent of the population can often be affected by these outbreaks, with young adults being most affected. Men often outnumber women, thought to be related to increased exposure to contaminated water [5].

In regions of the world with lower endemic rates, such as the USA, Western Europe, and developed countries of the Asia-Pacific, hepatitis E infection is quite infrequent [5]. Most are related to recent travel to endemic areas, but an occasional small foodborne outbreak due to locally acquired infection has occurred. Several observations, based on viral genomics, have led to the realization that zoonotic isolates (genotype 3 in the USA, genotype 4 in Asia) of hepatitis E can be spread to humans. This has been observed with ingestion of contaminated wild boar, wild deer and commercially available pig liver. This has led to sporadic outbreaks of hepatitis E in low endemic areas, which differ greatly than larger epidemic outbreaks seen in highly endemic areas [5].

Infectivity rates of hepatitis E are similar to hepatitis A. Viremia and fecal shedding of the hepatitis E virus begin 1–2 weeks prior to symptoms. Fecal shedding of virus lasts approximately 2–4 weeks after the onset of symptoms [4]. Incubation period ranges from 15 to 60 days.

Hepatitis A is a small, non-enveloped single-stranded RNA virus. Based on outbreaks and clinical presentation, it was initially thought to be an enterovirus [7]. In 1992, it was classified as a member of the Hepatovirus genus of the family Picornaviridae. This virus replicates inside the hepatocytes and interferes with liver function. This leads to an immune response, thus leading to liver inflammation [2].

Hepatitis E was also initially known as an enterically transmitted non-A, non-B hepatitis virus, which was subsequently named hepatitis E. It is classified in the genus Hepevirus and family Hepeviridae [7]. This family also includes related viruses that infect pigs, rabbits, rats, deer, and mongoose. Within the genus Hepevirus, at least four genotypes have been recognized; Genotype 1 and 2 are restricted to humans, while Genotype 3 and 4 have many hosts (including humans) and are zoonotic [5]. Interspecies transmission has been demonstrated, which has lead to sporadic outbreaks of hepatitis E in non-endemic areas of the world. The hepatitis E virions are small, non-enveloped single-stranded RNA, similar to hepatitis A [7]. This virus infects hepatocytes, leading to replication. It is not directly cytopathic, but instead leads to liver injury due to the host immune response [5].

What are the typical and atypical presentations of hepatitis A and E?

D.1 Signs and symptoms

D.2 Clinical spectrum from asymptomatic, to acute hepatitis, acute liver failure, relapsing and cholestatic hepatitis. Chronic hepatitis E in immunosuppressed populations.

D.3 Risk factors for severe outcome

D.4 Natural history of hepatitis A and hepatitis E self limited hepatitis

Hepatitis A and E both have clinical symptoms that are indistinguishable from other forms of acute hepatitis. Both present with nonspecific symptoms including fever, malaise, weakness, anorexia, nausea, vomiting, arthralgias, and myalgias. The prodromal symptoms tend to subside with the onset of jaundice. Jaundice is usually self-limited and lasts for a few weeks. Physical examination often will reveal jaundice, hepatomegaly, and splenomegaly. These are considered to be the typical manifestations of the disease and usually lead to a self-limited disease course [1, 2, 5].

For hepatitis A, symptomatology varies greatly with age. Around 50 % of children, under the age of 6 who become infected are asymptomatic [2]. Of those who do develop symptoms, most are mild and often not recognized to be related to hepatitis. Between 5 and 10 % of children, less than 6, who are infected develop jaundice. Beginning at age 6 and older, more than 75 % of patients develop hepatitis symptoms such as jaundice and dark urine [2].

There are also some atypical features of hepatitis A, which include relapsing hepatitis and prolonged cholestasis [8]. Relapsing hepatitis is characterized by a biphasic peak of serum aminotransferases, with a 4–7 week period in between the phases.

Prolonged cholestatic hepatitis A is characterized by prolonged jaundice often beyond 12 weeks, pruritus, fatigue, loose stools and weight loss in addition to cholestasis [8]. This manifestation can be predicted by detection of plasma hepatitis A RNA after 20 days of illness, while relapsing hepatitis cannot be predicted. Persistence of serum hepatitis A IgM antibodies in serum is also seen in cholestatic hepatitis A.