Overview
The liver is amongst the most important organs in the body, as it is responsible for detoxification, metabolism, synthesis of protein production, produce bile, and regulate immunity. The liver’s role in homeostasis makes it susceptible to any number of diseases; infections are among the most frequently associated with liver disease. One of the most common liver diseases of all is hepatitis, or inflammation of the liver, which is typically caused by a viral infection, but can also be caused by the consumption of alcohol, toxins, autoimmune disease, or a metabolic disease.
Hepatitis is a public health issue worldwide affecting millions of people every year. Once an individual develops chronic hepatitis infection, complications from chronic hepatitis can progress to complications of cirrhosis, liver failure, and/or hepatocellular carcinoma (cancer of the liver). Fortunately, modern medicine has developed effective preventive measures for hepatitis infection including vaccines, antiviral treatments, and behavior modification measures.
This article will discuss liver infections; however, viral hepatitis will be the prominent focus including a discussion of the types of hepatitis, cause of hepatitis, symptoms of hepatitis, complications of hepatitis, diagnosis of hepatitis, treatment of hepatitis, and prevention measures related to hepatitis.
Structure and Role of the Liver
In order to understand liver infections, an appreciation for the anatomy and functions of the liver is essential .
. Anatomy: The liver is an intra-abdominal organ situated in the upper right corner of the abdomen and under the diaphragm .
. Function :
. Detoxification of drugs, alcohol and toxins .
. Regulation of carbohydrate, fat, and protein metabolism.
. Storage of vitamins (A, D, E, K, B12) and minerals (iron, copper).
. Manufacture of bile which is required for the digestion of fats.
. Synthesis of clotting factors and various plasma proteins.
. Immune protection from pathogens through Kupffer cells phenotype.
Infection of the Liver: General Background
Liver infections can have many causes, but viral hepatitis is the most common form of infectious disease in the world. Other liver infections include parasitic infections (e.g., amoebic liver abscess), bacterial infections (e.g., cholangitis, leptospirosis), and fungal infections in immunocompromised patients.
Types of Liver Infectious Disease
1. Viral hepatitis – (A, B, C, D, E).
2. Alcoholic hepatitis – inflammation of the liver due to excessive alcohol ingestion.
3. Toxic hepatitis – from exposure to medications (e.g., acetaminophen toxicity), chemicals, or poisonous agents.
4. Autoimmune hepatitis – the immune system attacks the liver.
5. Parasitic infections – Entamoeba histolytica (amoebic abscess), Echinococus (hydatid disease).
6. Bacterial infections – pyogenic liver abscess, leptospirosis.
Viral hepatitis is the most common and potentially harmful form of infectious disease and requires effort on a global scale to prioritize prevention.
Types of Viral Hepatitis
Viral hepatitis can be categorized into five primary types, from viruses that cause hepatitis; viral hepatitis and viruses that cause liver disease is referred to as
1. Hepatitis A Virus (HAV)
. Route of transmission: Fecal–oral route, primarily through contaminated food, contaminated water, or poor personal hygiene, and sanitary practices.
. Incubation period: 2–6 weeks.
. Clinical course: Usually is acute and self-limited; has a low risk of becoming chronic with little to no risk of sustaining chronic liver disease.
. Symptoms: fatigue and malaise; nausea; jaundice; abdominal pain; dark urine.
. Prevention: availability of safe water, sanitation, and an effective vaccination.
2. Hepatitis B Virus (HBV)
. Route of transmission: a bloodborne route, unprotected sex, sharing of needles, mother-to-child during birth, blood transfusions.
. Incubation period: 6 weeks – 6 months.
. Clinical course: can be acute or chronic. Chronic HBV can cause cirrhosis of the liver and promote liver cancer.
. Symptoms: jaundice, loss of appetite, fatigue, abdominal pain, and joint pain.
. Prevention: Highly effective vaccination against HBV practicing safe sexual behaviors and blood screening practices.
3. Hepatitis C Virus HCV
. Route of transmission: bloodborne, mainly through sharing needles, unsafe medical procedures, or receipt of unscreened blood products.
. Clinical course: can be asymptomatic even when infected, especially during early phases of infection. Long-term cases will have a high risk of chronic infection.
. Complications: Cirrhosis of the liver and liver cancer in long-term cases.
. Prevention: Currently HCV has no vaccination available, and prevention relies on blood safety and hygiene with needles or shared medical practices .
4. Hepatitis D Virus (HDV)
. Transmission: Co-infection with HBV is required (HBV is required for replication).
. Severity: Produces more severe disease than HBV alone.
. Prevention: Prevention of HBV infection halts HDV infection.
5. Hepatitis E Virus (HEV)
. Transmission: Fecal–oral (contaminated water); particularly prevalent in developing countries.
. Clinical course: Usually acute and self-liging, but can be life threatening in pregnant women.
. Prevention: Safe drinking water, improved sanitation, and HEV vaccine (in the appropriate country).
Signs and Symptoms of Hepatitis
The course of hepatitis depends on the type of virus and the stage of infection, but signs common to all types of hepatitis include:
. Fatigue and weakness
. Loss of appetite
. Nausea and vomiting
. Abdominal pain (in particular the right upper quadrant)
. Jaundice (yellowing of skin and eyes)
. Dark urine and pale stool
. Itching of the skin
. Swelling of the legs and abdomen (in advanced cases, not seen in all cases)
In some patients, including many with HCV, and HBV, they retained such versatility and apparently unlimited systemic reserve that they may remain asymptomatic for years while silent liver damage progressed.”
Diagnosis of Liver Infections
Diagnosis usually consists of:
1. Medical record and physical examination .
2. Laboratory tests:
. Tests of liver function (ALT, AST, bilirubin, ALP).
. Serological markers for specific hepatitis viruses.
. Esitmation of viral load (HBV DNA, HCV RNA).
3. Radiographic studies: Ultrasound, CT, or MRI to detect hepatomegaly, fibrosis, or abscess.
4. Liver biopsy: To demonstrate liver damage, inflammation, or fibrosis.
Complications of Chronic Hepatitis
If untreated, chronic hepatitis (most commonly HBV and HCV) can lead to:
. Cirrhosis (scarring of the liver)
. Portal hypertension
. Liver failure
. Hepatocellular carcinoma (HCC)
. Co-infection (HIV, HDV) that complicate the presenting outcomes .
Liver Infection Treatments
Treatments depend on the cause of the infection:
, Hepatitis A & E: Supportive care; usually self-limiting.
. Hepatitis B: Antiviral drugs (tenofovir or entecavir); interferon therapy in select cases .
. Hepatitis C: Direct-acting antivirals (DAAs) resulting in cure rates above 95% .
. Hepatitis D: Pegylated interferon; management of HBV co-infection.
. Bacterial infections: Broad spectrum antibiotics and drainage of abscess if needed.
. Parasitic infections: Anti-parasitic medications (metronidazole for amoebiasis, albendazole for hydatid disease) .
Liver transplantation as needed in end-stage disease .
Hepatitis Prevention
The most effective way to reduce the overall burden of liver infections globally is through prevention.
General Preventive Measures
1. Vaccination:
. Effective vaccines exist for HAV and HBV (and by default for HDV).
. An HEV vaccine is produced in some countries.
. Currently, there is no vaccine for HCV.
2. Safe food and water practices:
. Boil or filter drinking water.
. Wash fruits and vegetables.
. Practice proper hand hygiene.
3. Safe medical practices:
. Use sterile syringes, needles, and other medical instruments.
. Screen blood donor.
. Avoid unnecessary injections.
4. Safe sexual practices:
. Use condoms.
. Limit sexual partners.
. Get tested for hepatitis before taking risks with unprotected sex.
5. Mother to child transmission prevention:
. Screen pregnant women for HBV.
. Give hepatitis B immunoglobulin and hepatitis B vaccine to infants born to infected mothers.
6. Harm reduction in drug use:
. Distribute clean needles and syringes.
. Encourage drug rehabilitation programs.
7. Education and awareness:
. Conduct public health campaigns on the risk and prevention of hepatitis.
. Encourage early testing and treatment.
The Global Burden of Hepatitis
. According to the World Health Organization (WHO) report:
. There were more than 354 million people living with chronic hepatitis B and C – combined – worldwide.
. Both hepatitis B and C combined resulted in 1.1 million deaths each year.
. A large number of people are asymptomatic for hepatitis because they have not been tested and do not know their status.
1. Hepatitis A Virus (HAV)
. Family: Picornaviridae
. Genus: Hepatovirus
. Genome: Single-stranded, positive-sense RNA (~7.5 kb).
. Structure: Non-enveloped, icosahedral capsid.
Replication
1. HAV enters hepatocytes upon binding to HAVCR1 (hepatitis A virus cellular receptor 1).
2. After uncoating, because the virus is positive-sense RNA, the viral RNA is directly translated by the host ribosomes.
3. The virus utilizes an internal ribosome entry site (IRES) to commandeer the host’s translation machinery.
4. Replication occurs in the cytoplasm and utilizes viral RNA-dependent RNA polymerase.
5. Assembly occurs in the cytoplasm and the virus is released in the two forms: naked particles (in fecal samples) and quasi-enveloped particles (in blood).
Immune Evasion
. To evade the immune system, HAV disguises itself to part of its life cycle in host-derived membranes (quasi-enveloped particles).
. HAV is incredibly stable in the environment and can even be found in food and water.
2. Hepatitis B Virus (HBV)
. Family: Hepadnaviridae
. Genome: Partially double-stranded DNA (~3.2 kb).
. Structure: Enveloped virus with a surface antigen (HBsAg), a core antigen (HBcAg), and an e antigen (HBeAg).
. Special characteristic: Replicates via reverse transcription; so it is a DNA virus replicating like a retrovirus, which is unusual for DNA viruses.
Replication
1. HBV infects hepatocytes by binding to the NTCP receptor.
2. The viral nucleocapsid is transported to the nucleus of the host cell, where the partially double-stranded viral genome is converted to cccDNA (covalently closed circular DNA).
3. The cccDNA serves as a template for the transcription of viral RNAs, mediated by the host’s RNA polymerase II.
4. The structural proteins, polymerase, and surface proteins are translated from viral mRNAs.
5. The viral polymerase promotes reverse transcription of the pregenomic RNA (pgRNA) into DNA.
6. The new nucleocapsids consisting of viral protein, and possibly some cccDNA, and viral DNA are either secreted into the plasma or recycled back to the nucleus to maintain the cccDNA (the source of infectious virus).
Immune Evasion
. The cccDNA persists in the nuclei of hepatocytes, thus HBV is that much more difficult to eradicate.
. HBsAg and HBeAg act as “immune decoys” and blunt host responses.
. HBV directly suppresses the innate immune signaling pathways that help to promote persistence or evade immune responses.
3. Hepatitis C Virus (HCV)
. Family: Flaviviridae
. Genus: Hepacivirus
. Genome: Positive-sense, single-stranded RNA (~9.6 kb).
. Structure: Enveloped, spherical particle with E1 and E2 glycoproteins.
Replication
1. Entry into hepatocytes begins with receptor binding involving molecules such as CD81, SR-B1, claudin‐1 and occludin.
2. Entry occurs through clathrin-mediated endocytosis.
3. Once in the cytoplasm, the viral RNA is released and translated into a single polyprotein of approximately 3000 amino-acids.
4. The polyprotein is cleaved by viral and host proteases into structural (C, E1, E2) and non-structural proteins (ns2, ns3, ns4A, ns4B, ns5A, ns5B).
5. Viral replication occurs on membranous webs within lipid droplet-associated membranes and within the cytoplasm.
6. Newly assembled virions are secreted via the very-low-density lipoprotein (VLDL) pathway; therefore, HCV particles are referred to as “lipoviroparticles.”
Immune Evasion
. The virus has a high degree of genetic variability due to the use of a low-fidelity (-error-prone) RNA polymerase that creates different viral quasispecies and offers a degree of immune escape.
. The N/S proteins prevent signaling by interferon.
. Finally, HCV inhibits the positive signaling of T-cell responses and antigen presentation leading to chronicity in most infections.
Frequently Asked Questions (FAQ)
- Is hepatitis curable?
Hepatitis A and E typically don’t require treatment. Most people have a self-limiting infection and recover in a few weeks.
Hepatitis B cannot be cured in most cases. However, it can be controlled. For those living with HBV, viral replication can be suppressed with potent antiviral agents. Controlling infection can reduce the risk of liver disease, liver cancer, and infectiousness.
Hepatitis C can be cured. The emergence of heretofore unencumbered and contemporary antiviral regimens have made the complete cure possible, usually within three months after onset.
Is hepatitis infectious?
Yes, it is. Both hepatitis A and E are transmitted through food and water. Hepatitis B, C, and D are transmitted through blood, blood products, sex, and mother-to-child.
How well do vaccines work against hepatitis?
Both HAV and HBV vaccines are very effective for long-term protection against future infection.
Can a person have hepatitis without any symptoms?
Yes. The majority of people living with HBV and HCV are asymptomatic (without clinical presentation) for many years while they have a progressive liver disease.
What foods do hepatitis patients need to avoid?
Avoid alcohol, fried foods, excessive sodium, and processed foods.
Technically, if a person has hepatitis, a better diet will include lots of fruits, vegetables (preferably fresh), some amount of lean protein, and plenty of whole grains.
Conclusion
Infectious diseases of the liver, especially viral hepatitis, continue to be a major global health concern. Despite advances in vaccines and therapeutics, millions of people continue to suffer from preventable infections due to lack of vaccination and/or use of all safe practices and/or awareness. To prevent hepatitis, a multi-layered approach must be utilized; there are numerous variables in managing hepatitis that include: serious vaccination services, safe sanitation practices, safe practice of heathcare services, informed public education on hepatitis & liver concerns, and access to diagnosis and treatment.
