1. Hepatitis A

Sven Pischke and Heiner Wedemeyer

The virus

Hepatitis A is an inflammatory liver disease caused by infection with the hepatitis A virus (HAV). HAV is a single-stranded 27 nm non-enveloped, icosahedral RNA virus, which was first identified by immune electron microscopy in 1973 (Feinstone 1973). The virus belongs to the hepadnavirus genus of the Picornaviridae. Recent structure-based phylogenetic analysis placed HAV between typical picornavirus and insect picorna-like viruses (Wang 2015). Recent work suggests a rodent origin of HAV based on a large screening for hepatoviruses in more than 200 small mammal species (Drexler 2015). HAV uses host cell exosome membranes as an envelope which leads to protection from antibody mediated neutralisation (Feng 2013) but also facilitates detection of HAV by plasmacytoid dendritic cells which are main sources for type I interferon during infection (Feng 2015). Of note, only blood but not bile HAV shows host-derived membranes.

Seven different HAV genotypes have been described, of which four are able to infect humans (Lemon 1992).

The positive-sense single-stranded HAV RNA has a length of 7.5 kb and consists of a 5’ non-coding region of 740 nucleotides, a coding region of 2225 nucleotides and a 3’ non-coding region of approximately 60 nucleotides.

Acute hepatitis A is associated with a limited type I interferon response (Lanford 2011), which may be explained by cleavage of essential adaptor proteins by an HAV protease-polymerase precursor (Qu 2011). Recently HAV has been shown to interact with the mitochondrial antiviral signaling (MAVS) protein resulting in interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation (Hirai-Yuki 2016). A dominant role of CD4+ T cells to terminate HAV infection has been established in HAV infected chimpanzees (Zhou 2012). However, in humans strong HAV-specific CD8 T cells have also been described, potentially contributing to resolution of infection (Schulte 2011). A failure to maintain these HAV-specific T cell responses could increase the risk for relapsing HAV.

Epidemiology

HAV infections occur worldwide, either sporadically or in epidemic outbreaks. An estimated 1.4 million cases of HAV infections occur each year. HAV is usually transmitted and spread via the faecal-oral route (Lemon 1985). Thus, infection with HAV occurs predominantly in areas of lower socioeconomic status and reduced hygienic standards, especially in low-income, tropical countries. Not surprisingly, a study investigating French children confirmed that travel to countries endemic for HAV is indeed a risk factor for the presence of anti-HAV antibodies (Faillon 2012). In high-income countries like the US or Germany the number of reported cases has decreased markedly in the past decades, according to official data published by the Centers for Disease Control and Prevention (CDC, Atlanta, USA) and the Robert Koch Institute (RKI, Berlin, Germany) (Figure 1). This decrease is mainly based on improved sanitary conditions as, e.g., recently demonstrated for Southern Italy (Zuin 2016). Moreover, vaccination programmes have also resulted in fewer HAV infections in various endemic countries including Argentina, Brazil, Italy, China, Russia, Ukraine, Spain, Belarus, Israel and Turkey (Hendrickx 2008).

Despite of the overall decrease in the frequency of hepatitis A in industrialised countries HAV outbreaks still occur. For example, HAV outbreaks have been described both in Europe and the US that were linked to frozen berries (Guzman Herrador 2014, Fitzgerald 2014) or imported pomegranate arils (Collier 2014). An outbreak of HAV was also described in Tel Aviv, Israel. Interestingly four of the patients (5%) had been previously vaccinated. In addition to the observed outbreak, HAV could be detected in sewage samples from various regions in Israel indicating the presence of this virus across Israel (Manor 2016).

Transmission

HAV is transmitted faecal-orally either by person-to-person contact or ingestion of contaminated food or water. Usually HAV is restricted to humans and is not considered to be a zoonosis. However, experimental HAV infection of pigs has been demonstrated (Song 2015). HAV transmission is also possible by blood transfusion but considered to be extremely rare (da Silva 2016).

Five days before clinical symptoms appear, the HAV can be isolated from the faeces of patients (Dienstag 1975). The virus stays detectable in the faeces up to two weeks after the onset of jaundice. Faecal excretion of HAV up to five months after infection can occur in children and immunocompromised persons. A recent study from Brazil evaluated the risk of household HAV transmission within a cohort of 97 persons from 30 families (Rodrigues-Lima 2013). Person-to-person transmission was seen in six cases indicating a relevant risk for relatives of patients with HAV. On the other hand, there was no evidence of HAV transmission in another incident by an HAV-infected food handler in London (Hall 2014). Further studies are necessary to evaluate the use of HAV vaccination of relatives at risk in this setting.

Risk groups for acquiring an HAV infection in high-income countries are health care providers, military personnel, psychiatric patients and men who have sex with men. Parenteral transmission by blood transfusion has been described but is a rare event. Mother-to-fetus transmission has not been reported (Tong 1981). Distinct genetic polymorphisms including variants in ABCB1, TGFB1, XRCC1 may be associated with a susceptibility to HAV (Zhang 2012).

Recently it was shown that the number of reported HAV infections in the USA decreased from 6 cases/ 100000 in 1999 to 0.4 cases/ 100000 in 2011, while the percentage of hospitalisations due to HAV increased from 7.3% to 24.5% indicating that HAV is becoming a rare condition but can still cause serious morbidity, especially in elderly and patients with underlying liver disorders (Ly 2015). In line with this report the overall immunity to HAV is declining in United States (Klevens 2015) suggesting that vaccination coverage needs to be improved.

Clinical course

The clinical course of HAV infection varies greatly, ranging from asymptomatic, subclinical infections to cholestatic hepatitis or fulminant liver failure (Figure 2).

Most infections in children are either asymptomatic or unrecognised, while 70% of adults develop clinical symptoms of hepatitis with jaundice and hepatomegaly.

The incubation time ranges between 15 and 49 days with a mean of approximately 30 days (Koff 1992). Initial symptoms are usually non-specific and include weakness, nausea, vomiting, anorexia, fever, abdominal discomfort, and right upper quadrant pain (Lednar 1985). As the disease progresses, some patients develop jaundice, darkened urine, uncoloured stool and pruritus. The prodromal symptoms usually diminish when jaundice appears.

Approximately 10% of infections take a biphasic or relapsing course. In these cases the initial episode lasts about 3–5 weeks, followed by a period of biochemical remission with normal liver enzymes for 4–5 weeks. Relapse may mimic the initial episode of the acute hepatitis and complete normalisation of ALT and AST values may take several months (Tong 1995). A recent investigation in two HAV-infected chimpanzees demonstrated that the CD4 count decreased after clinical signs of HAV disappeared (Zhou 2012). Eventually, an intrahepatic reservoir of HAV genomes that decays slowly in combination with this CD4 response, may explain the second phase of disease, but further observations on human patients are required to verify this.

Cases of severe fulminant HAV leading to hepatic failure occur more often in patients with underlying liver disease. Conflicting data on the course of acute HAV have been reported for patients with chronic hepatitis C (HCV). While some studies showed a higher incidence of fulminant hepatitis (Vento 1998), other studies do not confirm these findings and even suggest that HAV superinfection may lead to clearance of HCV infection (Deterding 2006). Other risk factors for more severe courses of acute HAV are age, malnutrition and immunosuppression. Severity of liver disease during acute HAV has recently been shown to be associated with a distinct polymorphism in TIM1, the gene encoding for the HAV receptor (Kim 2011). An insertion of six amino acids at position 157 of TIM1 leads to more efficient HAV binding and greater NKT lytic activity against HAV infected liver cells.

In contrast to hepatitis E, there are no precise data on the outcome of HAV infection during pregnancy. Some data suggest an increased risk of gestational complications and premature birth (Elinav 2006).

HAV has a lethal course in 0.1% of children, in 0.4% of persons aged 15–39 years, and in 1.1% in persons older than 40 years (Lemon 1985). In contrast to the other faecal-orally transmitted hepatitis (hepatitis E), no chronic courses of HAV infection have been reported so far.

Extrahepatic manifestations

Extrahepatic manifestations are uncommon in HAV (Pischke 2007). If they occur, they usually show an acute onset and disappear upon resolution of HAV infection in most cases. Possible extrahepatic manifestations of acute HAV infection are arthralgia, diarrhoea, renal failure, red cell aplasia, generalised lymphadenopathy, and pancreatitis. Arthralgia can be found in 11% of patients with hepatitis A.

Very uncommon are severe extrahepatic manifestations like pericarditis and/or renal failure. An association of hepatitis A with cryoglobulinaemia has been reported but is a rare event (Schiff 1992). Furthermore, cutaneous vasculitis can occur. In some cases, skin biopsies reveal anti-HAV-specific IgM antibodies and complements in the vessel walls (Schiff 1992). In contrast to hepatitis B or C, renal involvement is rare, and there are very few case reports showing acute renal failure associated with HAV infection (Pischke 2007). Recently it has been shown that approximately 8% of HAV cases are associated with acute kidney injury (Choi 2011).

Diagnosis

Diagnosis of acute HAV is based on the detection of anti-HAV IgM antibodies or HAV RNA. The presence of HAV IgG antibodies can indicate acute or previous HAV infection. HAV IgM and IgG antibodies also become positive early after vaccination, with IgG antibodies persisting for at least two to three decades after vaccination. Antibodies against HAV and HAV RNA can also be detected in saliva (Amado Leon 2015). Available serological tests show a very high sensitivity and specificity. Recently, a study from Taiwan revealed that HIV-infected patients develop protective antibody titres after HAV vaccination less frequently than healthy controls (Tseng 2012). In addition a study examining the immune response to HAV vaccination in 282 HIV positive patients (Mena 2013) demonstrated that male sex or HCV coinfection were associated with lower response rates. Furthermore, it was shown that in people living with HIV, HAV vaccination with three doses results in an improved durability of antibodies in comparison with two-dose vaccination (Cheng 2016), while a Nicaraguan study on children demonstrated that one-dose vaccination resulted in an adequate long-term immune memory (Mayorga 2016).

A large study investigated 183 adolescents (age 15 to 16 years) who had been vaccinated with a two-dose HAV vaccination at an age of 6, 12 or 15 months. Seropositivity was lower in children who were vaccinated at 6 months as well as in children where maternal HAV antibodies were transferred (Spradling 2015). This study demonstrates that HAV vaccination should usually be performed after 12 months of age, which is in line with the current US recommendations. Delayed seroconversion may occur in immunocompromised individuals, and testing for HAV RNA should be considered in immunosuppressed individuals with unclear hepatitis. HAV RNA testing of blood and stool can determine if the patient is still infectious. However, it has to be kept in mind that various in-house HAV RNA assays may not be specific for all HAV genotypes and thus false negative results can occur.

Elevated results for serum aminotransferases and serum bilirubin can be found in symptomatic patients (Tong 1995). ALT levels are usually higher than serum aspartate aminotransferase (AST) in non-fulminant cases. Increased serum levels of alkaline phosphatase and gamma-glutamyl transferase indicate a cholestatic form of HAV infection. The increase and the peak of serum aminotransferases usually precede the increase of serum bilirubin. Laboratory markers of inflammation, like an elevated erythrocyte sedimentation rate and increased immunoglobulin levels, can also frequently be detected.

Recently within a small pilot study, examining 10 patients with acute HAV, saliva contained HAV RNA in 8/10 (80%) and anti HAV IgM in 10/10 (100%) (Armado Leon 2014). The relevance of this finding and the potential value of saliva testing needs to be studied in larger cohorts.

Treatment and prognosis

There is no specific antiviral therapy for treatment of HAV. Of note, recent work demonstrated that cyclosporine A and silibinin inhibits HAV replication in vitro (Esser-Nobis 2015). The clinical value of this observation still needs to be determined.

Recently a study from the Netherlands investigated the use of post-exposure HAV vaccination or prophylaxis with immunoglobulins in patients with household contact with HAV. In this study, none of the patients who received immunoglobulins developed acute HAV in contrast to some patients who received the vaccine. The study revealed that HAV vaccination post-exposure might be a sufficient option in younger patients (<40 years) while older patients (>40 years) might benefit from immunoglobulins (Whelan 2013). The disease usually takes a mild to moderate course, which does not require hospitalisation, and only in fulminant cases is initiation of symptom focused therapy necessary. Prolonged or biphasic courses should be monitored closely. HAV may persist for some time in the liver even when HAV RNA becomes negative in blood and stool (Lanford 2011), which needs to be kept in mind for immunocompromised individuals. Acute hepatitis may rarely proceed to acute liver failure; liver transplantation is required in few cases. In the US, only 4% of all liver transplantations performed for acute liver failure were due to HAV (Ostapowicz 2002). In a cohort of acute liver failures at one transplant centre in Germany, approximately 1% of patients had HAV infection (Hadem 2008). The outcome of patients after liver transplantation for fulminant HAV is excellent. Timely referral to liver transplant centres is therefore recommended for patients with severe or fulminant HAV.

References

Armado Leon La, de Almeida AJ, de Paula VS et al. Longitudinal Study of Hepatitis A Infection by Saliva Sampling: The Kinetics of HAV Markers in Saliva Revealed the Application of Saliva Tests for Hepatitis A Study. PLOS One 2015; 10(12).

Centers for Disease Control and Prevention. Viral Hepatitis Surveillance – United States 2010. Hepatitis A virus, http://www.cdc.gov/hepatitis/Statistics/index.htm, accessed 26 January 2013.

Cheng A, Chang SY, Sun HY, et al. Long-term durability of responses to 2 or 3 doses of hepatitis A vaccination in HIV positive adults on antiretroviral therapy. J Infect Dis. 2016 Dec 23. pii: jiw605.

Choi HK, Song YG, Han SH, et al. Clinical features and outcomes of acute kidney injury among patients with acute hepatitis A. J Clin Virol 2011;52:192-7.

Collier MG, Khudyakov YE, Selvage D, et al. Outbreak of hepatitis A in the USA associated with frozen pomegranate arils imported from Turkey: an epidemiological case study. Lancet Infect. Dis. 2014; 10: 976-981.

da Silva SG, Leon LA, Alves G, et al. Rare Case of Transfusion Transmission of Hepatitis A Virus to Two Patients with Haematological Disease. Transfus Med Hemother. 2016 Mar;43(2):137-41.

Deterding K, Tegtmeyer B, Cornberg M, et al. Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV. J Hepatol 2006;45:770-8.

Dienstag JL, Feinstone SM, Kapikian AZ, Purcell RH. Faecal shedding of hepatitis-A antigen. Lancet 1975;1:765-7.

Drexler JF, Corman VM, Lukashev AN, et al. Hepatovirus Ecology Consortium. Evolutionary origins of hepatitis A virus in small mammals. Proc Natl Acad Sci U S A. 2015;112:15190-5. 

Elinav E, Ben-Dov IZ, Shapira Y, et al. Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor. Gastroenterology 2006;130:1129-34.

Esser-Nobis K, Harak C, Schult P, et al. Hepatology 2015, 62: 397-408.

Faillon S, Martinot A, Hau I, et al. Impact of travel on the seroprevalence of hepatitis A in children. J Clin Virol. 2013 Jan;56(1):46-51. doi: 10.1016/j.jcv.2012.10.004.

Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science 1973;182:1026-8.

Feng Z, Hensley L, McKnight KL, et al. A pathogenic picornavirus acquires an envelope by hijacking cellular membranes. Nature. 2013;496(7445):367-71.

Feng Z, Li Y, McKnight KL, et al. Human pDCs preferentially sense enveloped hepatitis A virions. J Clin Invest. 2015;125:169-76.

Fitzgerald M, Thornton L, O’Gorman J, et al. Outbreak of hepatitis A infection associated with the consumption of frozen berries, Ireland, 2013 - linked to an international outbreak. Euro Surveill. 2014;19(43):pii=20942.

Guzman-Herrador B, Jensvoll L, Einöder-Moreno M, et al. Ongoing hepatitis A outbreak in Europe 2013 to 2014: imported berry mix cake suspected to be the source of infection in Norway . Euro Surveill. 2014;19(15):pii=20775.

Hadem J, Stiefel P, Bahr MJ, et al. Prognostic implications of lactate, bilirubin, and aetiology in German patients with acute liver failure. Clin Gastroenterol Hepatol 2008;6:339-45.

Hall V, Abrahams A, Tubitt D, et al. No evidence of transmission from an acute case of hepatitis E in a foodhandler: follow-up of almost 1000 potentially exposed individuals, Lonndon, United Kingdom, April 2012Euro Surveill. 2014; 19 (30).

Hendrickx G, Van Herck K, Vorsters A, et al. Has the time come to control hepatitis A globally? Matching prevention to the changing epidemiology. J Viral Hepat 2008;15 Suppl 2:1-15.

Hirai-Yuki A, Hensley L, McGivern DR, et al. MAVS-dependent host species range and pathogenicity of human hepatitis A virus.Science 2016; 1541-1545.

Kim HY, Eyheramonho MB, Pichavant M, et al. A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans. J Clin Invest. 2011;121:1111-8.

Klevens RM, Denniston MM, Jiles-Chapman RB, Murphy TV. Decreasing immunity to hepatitis A virus infection among US adults: Findings from the National Health and Nutrition Examination Survey (NHANES), 1999-2012. Vaccine. 2015;33:6192-8. 

Koff RS. Clinical manifestations and diagnosis of hepatitis A virus infection. Vaccine 1992;10 Suppl 1:S15-7.

Lanford RE, Feng Z, Chavez D, et al. Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl Acad Sci U S A 2011;108:11223-8.

Lednar WM, Lemon SM, Kirkpatrick JW, Redfield RR, Fields ML, Kelley PW. Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol 1985;122:226-33.

Lemon SM, Jansen RW, Brown EA. Genetic, antigenic and biological differences between strains of hepatitis A virus. Vaccine 1992;10 Suppl 1:S40-4.

Lemon SM. Type A viral hepatitis. New developments in an old disease. N Engl J Med 1985;313:1059-67.

Ly KN, Klevens RM. Trends in disease and complications of hepatitis A virus infection in the United States 199-2011: a new concern for adults. J. Infect. Dis. 2015, 58; 40-49.

Manor Y, Lewis M, Ram D, et al. Evidence for Hepatitis A virus endemic circulation in Israel despite universal toddlers’ vaccination since 1999 and low clinical incidence in all age groups. J Infect Dis. 2016 Dec 24 jiw611.

Mayorga O, Bühler S, Jaeger VK, et al.Single-Dose Hepatitis A Immunization: 7.5-Year Observational Pilot Study in Nicaraguan Children to Assess Protective Effectiveness and Humoral Immune Memory Response. J Infect Dis (2016) 214 (10): 1498-1506.

Mena G, García-Basteiro AL, Llupià A, Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy. Vaccine. 2013;12;31(36):3668-74.

Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-54.

Pischke S, Vogel A, Jaeckel E, Manns MP. Immunopathogenesis of Extrahepatic Manifestations in HAV, HBV, and HCV Infections. In: Liver Immunology. Totowa, New Jersey: Humana Press, 2007:209-17.

Rodrigues-Lima L, De Ameilda AJ, dos Santos Tourinho R, et al. Evidence of Hepatitis A Virus Person-to-Person Transmission in Household Outbreaks. PLOS One 2013, Vol. 9, Issue 7.

Qu L, Feng Z, Yamane, et al. Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD. PLoS Pathog. 2011 Sep;7(9):e1002169.

Schiff ER. Atypical clinical manifestations of hepatitis A. Vaccine 1992;10 Suppl 1:S18-20.

Schulte I, Hitziger T, Giugliano S, et al. Characterization of CD8+ T-cell response in acute and resolved hepatitis A virus infection. J Hepatol. 2011;54:201-8.

Song YJ, Park WJ, Park BJ, et al. Experimental evidence of hepatitis A virus infection in pigs. J. Med. Virol. 2015, :631-8.

Spradling PR, Bulkow LR, Negus SE, et al. Persistence of seropositivity among persons vaccinated for hepatitis A during infancy by maternal antibody status: 15 year follow-up- Hepatology 2015, 703-11.

Tseng YT, Chang SY, Liu WC, et al. Comparative effectiveness of two doses versus three doses of hepatitis a vaccine in HIV-infected and HIV-uninfected men who have sex with men. Hepatology 2013;57(5):1734-41.

Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis 1995;171 Suppl 1:S15-8.

Tong MJ, Thursby M, Rakela J, McPeak C, Edwards VM, Mosley JW. Studies on the maternal-infant transmission of the viruses which cause acute hepatitis. Gastroenterology 1981;80:999-1004.

Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998;338:286-90.

Wang X, Ren J, Gao Q, et al. Hepatitis A virus and the origin of picornaviruses. Nature 2015;517:85-8.

Whelan J, Sonder GJ, Bovee L, et al. Evaluation of hepatitis A vaccine in post-exposure prophylaxis, The Netherlands, 2004-2012. PLoS One 2013, 17: e78914.

Zhou Y, Callendret B, Xu D, et al. Dominance of the CD4(+) T helper cell response during acute resolving hepatitis A virus infection. J Exp Med. 2012 Jul 30;209(8):1481-92. doi: 10.1084/jem.20111906.

Zhang L, Yesupriya A, Hu DJ, et al. Variants in ABCB1, TGFB1, and XRCC1 genes and susceptibility to viral hepatitis A infection in Mexican Americans. Hepatology. 2012; 55:1008-18.

Zuin M, Caserta C, Romanò L, et al. Seroepidemiology of HEV and HAV in two populations with different socio-economic levels and hygienic/sanitary conditions. Eur J Clin Microbiol Infect Dis (2016). doi:10.1007/s10096-016-2821-7.