Synonym: infectious hepatitis
Hepatitis A virus (HAV)
HAV is a picornavirus
Review (original in German)
The virus responsible for hepatitis A--hepatitis A virus (HAV)--is a small, spherical, and exceptionally resistant RNA-virus. It is transmitted preferentially by the faecal-oral route and apparently replicates exclusively in the liver. The damage of the liver ensuing from HAV infection most likely does not stem directly from virus replication but is the result of an interaction of cell mediated virus-specific immunity with infected hepatocytes. Infection is usually self limiting, yet, in individual cases may also take a protracted and even relapsing course. True chronic infections, however, are not observed. HAV has a world-wide distribution. In countries where inadequate sanitary conditions prevail, the virus persists in the environment and almost 100% of the population acquires infection in childhood. At that age, infection causes no or only minimal clinical symptoms. Infected individuals nevertheless develop protective, long lasting immunity, probably persisting for entire life. In developed, industrialized countries HAV has ceased to circulate in the environment and the general population. Here, infections predominantly occur in adults travelling to endemic areas or exposed at home to thus infected individuals or members of high risk groups (e.g. children in day care centres, i.v. drug users). With increasing age infections become more and more clinically manifest and at and beyond of adolescence more than 80% of patients develop icteric, in some cases even fulminant and fatal hepatitis. Acute hepatitis A infection can be diagnosed by demonstrating the presence of anti-HAV-IgM antibodies. Immunity following either infection or successful vaccination is assessed by measuring anti-HAV-IgG. Preventive measures rely on strict personal and alimentary hygiene as well as on vaccination with inactivated (killed) hepatitis A vaccines. These vaccines are safe, highly immunogenetic and induce long lasting (> 20 years) protection against hepatitis A. Specific antiviral therapy is not yet available.
Introduction
Hepatitis A (formerly known as infectious hepatitis) is an acute infectious disease of the liver. It is caused by the hepatitis A virus (HAV). The HAV is an RNA virus. It is usually spread by the fecal-oral route. It can be transmitted person-to-person by ingestion of contaminated food or water. It can be contracted through direct contact with an infectious person.
Tens of millions of individuals worldwide are estimated to become infected with HAV each year. The time between infection and the appearance of the symptoms (the incubation period) is between two and six weeks and the average incubation period is 28 days.
In developing countries, and in regions with poor standards of hygiene, the incidence of infection with HAV is high. The illness is usually contracted in early childhood. As incomes rise and access to clean water increases, the incidence of HAV decreases. Hepatitis A infection causes no clinical signs and symptoms in over 90% of infected children. The infection confers lifelong immunity. The disease is of no special significance to those infected early in life.
In more developed countries, in Europe, the USA and other industrialized countries, the infection is contracted primarily by susceptible young adults. Most of whom are infected with the virus during trips to countries with a high incidence of the disease. They can also contract HAV through contact with infectious persons.
HAV infection produces a self-limited disease that does not result in chronic infection or chronic liver disease. However, 10–15% of patients might experience a relapse of symptoms during the 6 months after acute illness.
Acute liver failure from Hepatitis A is rare (overall case-fatality rate: 0.5%). The risk for symptomatic infection is directly related to age, with more than 80% of adults having symptoms compatible with acute viral hepatitis and the majority of children having either asymptomatic or unrecognized infection. Antibody produced in response to HAV infection persists for life and confers protection against reinfection. The disease can be prevented by vaccination. Hepatitis A vaccines have been proven effective in controlling outbreaks worldwide.
Signs and symptoms
Early symptoms of hepatitis A infection can be mistaken for influenza. Some sufferers, especially children, exhibit no symptoms at all. Symptoms typically appear 2 to 6 weeks (the incubation period) after the initial infection.
Symptoms usually last less than 2 months, although some people can be ill for as long as 6 months:
- Fatigue
- Fever
- Nausea
- Loss of appetite (LOA)
- Jaundice, a yellowing of the skin or whites of the eyes (sclarae) due to hyperbilirubinemia
- Bile is removed from blood stream and excreted in urine, giving it a dark amber colour
- Diarrhea
- Clay-coloured faeces (lacking the usual brown pigment)
Virology
Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine. The blood carries the virus to its target, the liver, where it multiplies within hepatocytes (liver cells) and Kupffer cells (liver macrophages).
Virions are secreted into the bile (hempedu) and released in stool. HAV is excreted in large quantities approximately 11 days prior to appearance of symptoms or anti-HAV IgM antibodies in the blood.
The incubation period is 15–50 days and mortality is less than 0.5%. Within the liver hepatocytes the RNA genome is released from the protein coat and is translated by the cell's own ribosomes.
Unlike other members of the Picornaviruses this virus requires an intact eukaryote initiating factor 4G (eIF4G) for the initiation of translation. The requirement for this factor results in an inability to shut down host protein synthesis unlike other picornaviruses.
The virus must then inefficiently compete for the cellular translational machinery which may explain its poor growth in cell culture. Presumably for this reason the virus has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host. Precisely how this strategy works is not quite clear yet.
There is no apparent virus-mediated cytotoxicity presumably because of the virus' own requirement for an intact eIF4G and liver pathology is likely immune-mediated.
Structure
The Hepatitis A virus (HAV) is a Picornavirus; it is non-enveloped and contains a single-stranded RNA packaged in a protein shell. There is only one serotype of the virus, but multiple genotypes exist. Codon use within the genome is biased and unusually distinct from its host. It also has a poor internal ribosome entry site. In the region that codes for the HAV capsid, there are highly conserved clusters of rare codons that restrict antigenic variability.
Transmission
The virus spreads by the fecal-oral route. Infections often occur in conditions of poor sanitation and overcrowding. Hepatitis A can be transmitted by the parenteral route but very rarely by blood and blood products.
Food-borne outbreaks are not uncommon. Ingestion of shellfish cultivated in polluted water is associated with a high risk of infection. Approximately 40% of all acute viral hepatitis is caused by HAV.
Infected individuals are infectious prior to onset of symptoms, roughly 10 days following infection.
The virus is resistant to detergent, acid (pH 1), solvents (e.g., ether, chloroform), drying, and temperatures up to 60 °C. It can survive for months in fresh and salt water.
Common-source (e.g., water, restaurant) outbreaks are typical.
Infection is common in children in developing countries, reaching 100% incidence, but following infection there is lifelong immunity.
HAV can be inactivated by: chlorine treatment (drinking water), formalin (0.35%, 37 °C, 72 hours), peracetic acid (2%, 4 hours), beta-propiolactone (0.25%, 1-hour), and UV radiation (2 μW/cm2/min).
Diagnosis
(i) Serum IgG and IgM
Two antibodies are used to detect HAV infection, HAV-specific IgM and HAV-specific IgG. Antibodies to HAV (anti-HAV) in the blood are a marker of past or current infection.
- HAV-specific IgM are used to detect present HAV infection.
- HAV-specific IgG are used to detect past HAV infection.
Although HAV is excreted in the faeces towards the end of the incubation period, specific diagnosis is made by the detection of HAV-specific IgM antibodies in the blood. IgM antibody is only present in the blood following an acute hepatitis A infection. It is detectable from one to two weeks after the initial infection and persists for up to 14 weeks.
The presence of IgG antibody in the blood means that the acute stage of the illness is past and the person is immune to further infection. IgG antibody to HAV is also found in the blood following vaccination and tests for immunity to the virus are based on the detection of this antibody.
(ii) Hepatitis serological panel
Serological markers of acute hepatitis: HBsAg, HBcIgM, anti-HCV, HEV-IgM, and HAV-IgM.
Serological markers of chronic hepatitis: HBsAg, HBcIgG, HBeAg, and anti-HCV.
(iii) Serum ALT
During the acute stage of the infection, the liver enzyme alanine transferase (ALT) is present in the blood at levels much higher than is normal. The enzyme comes from the liver cells (hepatocytes) that have been damaged by the virus.
(iv) EM: Presence of HAV particles in blood and faeces
HAV is present in blood and faeces. It can be detected by electron microscopy (EM).
Hepatitis A virus is present in the blood (viremia) and faeces of infected people up to two weeks before clinical illness develops.
Prevention
Hepatitis A can be prevented by vaccination, good hygiene and sanitation.
For information about the vaccine, its properties, and its application, see Hepatitis A vaccine.
There are two types of vaccines: one containing inactivated hepatitis A virus, and another containing a live but attenuated virus.
Both provide active immunity against a future infection.
The vaccine protects against HAV in more than 95% of cases for longer than 25 years.
In the USA the vaccine was first phased in 1996 for children in high-risk areas, and in 1999 it was spread to areas with elevating levels of infection.
The vaccine is given by injection.
An initial dose provides protection starting two to four weeks after vaccination; the second booster dose, given six to twelve months later, provides protection for over twenty years.
Vaccination programmes
The vaccine was introduced in 1992 and was initially recommended for persons at high risk.
Since then Bahrain and Israel have embarked on eradication programmes.
Australia, China, Belarus, Italy, Spain and the USA have started similar programmes.
The incidence of hepatitis A where widespread vaccination has been practised has decreased dramatically.
In China and the USA the incidence of hepatitis A has decreased by 90% since 1990.
Treatment
There is no specific treatment for hepatitis A.
(i) The normal doctors' advice
Sufferers are advised to rest, avoid fatty foods and alcohol (these may be poorly tolerated for some additional months during the recovery phase and cause minor relapses), eat a well-balanced diet, and stay hydrated.
(ii) Traditional Malay advice
In the Malay World, the elderly will advise to take fresh goat's milk with infusion of the
dukung anak plant. These are taken twice a day. This clears HAV infection within 2 weeks (as opposed to 1 month in the usual course of HAV clearance). The
dukung anak plant is a common garden weed.
Prognosis
The United States Centers for Disease Control and Prevention (CDC) in 1991 reported a low mortality rate for hepatitis A of 4 deaths per 1000 cases for the general population but a higher rate of 17.5 per 1000 in those aged 50 and over.
The risk of death from acute liver failure following HAV infection increases with age and when the person has underlying chronic liver disease.
Young children that are infected with hepatitis A typically have a milder form of the disease, usually lasting from 1–3 weeks, whereas adults tend to experience a much more severe form of the disease.
Epidemiology
High-income regions (Western Europe, Australia, New Zealand, Canada, the United States, Japan, the Republic of Korea, and Singapore) have very low HAV endemicity levels and a high proportion of susceptible adults.
Low-income regions (sub-Saharan Africa and parts of South Asia) have high endemicity levels and almost no susceptible adolescents and adults.
Most middle-income regions have a mix of intermediate and low endemicity levels.
Anti-HAV prevalence suggest that middle-income regions in Asia, Latin America, Eastern Europe, and the Middle East currently had an intermediate or low level of endemicity in 2005. The countries in these regions may have an increasing burden of disease from hepatitis A.
Globally, in 2010, acute hepatitis A resulted in 102,000 deaths which is slightly up from 99,000 in 1990.
There were 30,000 cases of Hepatitis A reported to the CDC in the U.S. in 1997. There were as many as 270,000 cases each year from 1980 through 2000.
Approximately one third of the US population has been infected by hepatitis A, most of whom go undiagnosed.
Genotypes
Only one serotype and seven different genetic groups (four humans and three simian) have been described.
The human genotypes are numbered I-III. Six subtypes have been described (IA, IB, IIA, IIB, IIIA, IIIB).
The simian (monkey) genotypes have been numbered IV-VI.
A single isolate of genotype VII isolated from a human has also been described.
Genotype III has been isolated from both humans and owl monkeys.
Most human isolates are of genotype I. Of the type I isolates subtype IA accounts for the majority. The mutation rate in the genome has been estimated to be 1.73 - 9.76 x 10−4 nucleotide substitution per site per year.
Cases
(i) USA - tainted green onions
The most widespread hepatitis A outbreak in the 2003 United States hepatitis outbreak afflicted at least 640 people (killing four) in north-eastern Ohio and south-western Pennsylvania in late 2003. The outbreak was blamed on tainted green onions at a restaurant in Monaca, Pennsylvania.
(ii) USA - recall of frozen berries
In June 2013, frozen berries sold by US retailer Costco and purchased by around 240,000 people were the subject of a recall, after at least 158 people were infected with HAV, 69 of whom were hospitalized.
(iii) China - contaminated river clams
In 1988, more than 300,000 people in Shanghai, China were infected with HAV after eating clams (
Anadara subcrenata) from a contaminated river.
(iv) Italy
During the period 1985-1994, 25553 viral hepatitis cases were reported. Of these, 6408 (25%) were due to hepatitis A (HAV).
(v) Brazil
The prevalence of hepatitis A varies greatly in different Brazilian regions, from 56% in South and Southeast to 93% in North region (Manaus, Amazon). Such differences are also found in different socioeconomic levels among age groups.
(vi) India
Hepatitis A (HAV) is endemic in India and most of the population is infected asymptomatically in early childhood with lifelong immunity. Because of altered epidemiology and decreasing endemicity, the pattern of acute HAV infection is changing from asymptomatic childhood infection to an increased incidence of symptomatic disease in the 18-40 age group. Sera collected from 3495 patients with acute (1932) and chronic (1563) liver disease attending the Medical Outpatient Department of Lok Nayak Hospital during the previous five years (1999-2003) were tested for various serological markers of acute (HBsAg, HBcIgM, anti-HCV, HEV-IgM, and HAV-IgM) and chronic (HBsAg, HBcIgG, HBeAg, and anti-HCV) hepatitis. In addition, 500 normal healthy attendants of the patients above the age of 15 years were tested for IgG anti-HAV as controls. Of 1932 patients with acute viral hepatitis, 221 (11.4%) were positive for immunoglobulin M (IgM) anti-HAV. The patients who were IgM anti-HAV negative included hepatitis B (321 patients), C (39 patients), E (507 patients) and unclassified (844 patients). Although the frequency of HAV infection among children had increased (10.6% to 22.0%) in the 5-year period, the frequency of HAV infection among adults had also increased (3.4% to 12.3%) during the same period. A total of 300 patients with chronic liver diseases that were etiologically related to hepatitis B (169), C (73) or dual infection (10) and alcoholic liver injury (48) were tested for the presence of IgG anti-HAV antibody; 98% (294/300) were positive for the antibody. Although universal vaccination against HAV is not currently indicated, selective vaccination of the high-risk population, based on their serological evidence of HAV antibody, would be a rational and cost-effective approach.
(vii) Argentina
Hepatitis A virus (HAV) has shown intermediate endemicity in Argentina. Its incidence has decreased since the HAV vaccine was introduced in 2005. Environmental surveillance was conducted in 5 rivers from Argentina from 2005 to 2012. HAV detection decreased since 2005. It is being circulated, maintaining viral diversity but not undergoing antigenic drift. Most sequences belonged to subgenotype IA, closely related to Argentinean clinical sequences. However, one belonged to proposed subgenotype IC, previously undetected in the country. Environmental surveillance might contribute to monitoring the single-dose vaccination schedule.
Implications of HAV infection to Malaysian food imports
Malaysia imports its beef or beef cattles from Argentina and India. It is important that the Malaysian authorities are strict with hepatitis A infection in frozen beef (daging beku) coming from overseas. Malaysia's high beef consumption hovers around the two festive seasons that are celebrated nationwide -
Aidilfitri and
Aidiladha.
Malaysians have started consuming milk and milk products from overseas since the 1980s. They include fresh and flavoured milk, ice-creams, yoghurts and yoghurt drinks. Food poisoning has been reported from primary schools but there are no reports of HAV infection from dairy produce.
External links
http://en.wikipedia.org/wiki/Hepatitis_A
Southscience.pbworks.com: "Hepatitis A."
Health-advisors.org: "Hepatitis-a-symptoms."
Abcnews.go.com: "Frozen-berries-recalled-over-hepatitis-fears."
Food.com: "Green-onion."
Sciencedirect.com/Clinical course and consequences of hepatitis A infection."
http://www.ncbi.nlm.nih.gov/pubmed/10683554
http://www.ncbi.nlm.nih.gov/pubmed/9126784
http://www.ncbi.nlm.nih.gov/pubmed/15771857
http://www.ncbi.nlm.nih.gov/pubmed/14579471
http://www.ncbi.nlm.nih.gov/pubmed/16677154
http://www.ncbi.nlm.nih.gov/pubmed/23072283
Emedicinehealth.com: "Hepatitis A Symptoms."
