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Hepatitis, the inflammation of the liver, is usually caused by viruses, bacteria, parasites, chemical poisons, drugs, alcohol, autoimmunity and other factors. These pathogenic factors destroy liver cells, causing impaired liver function.
According to pathogeny, hepatitis can be divided into viral hepatitis, alcoholic and drug-induced hepatitis, fatty liver, autoimmune hepatitis, etc.
Among these hepatitis, viral hepatitis is still the most common cause of hepatitis. The following mainly introduces the knowledge related to viral hepatitis.
Figure 1 Viral hepatitis
The concept of ischemic hepatitis (IH) was first proposed by Bynum et al [1] in 1979, which means that in the absence of any known cause of acute hepatitis, hepatocytes appear to be damaged. It is characterized by an acute, transient (5-25d) increase in aminotransferase levels (20 times higher than normal).
The diagnosis of this disease requires the exclusion of other causes of hepatocyte damage, and can be further confirmed by histological observation of obvious necrosis of the hepatic lobules central cells [2].
Autoimmune hepatitis (AIH) is a very typical chronic hepatobiliary disease, mainly due to a patient's autoimmune abnormalities, resulting in a chronic inflammation of the liver mediated by autoimmune response.
Autoimmune hepatitis is considered a disease associated with genetic and immune abnormalities. Studies have shown that hepatitis virus (A, B, C), herpes simplex virus (HSV) and other viral infections can induce autoimmune hepatitis, leading to liver cell damage [3]. AIH is involved in the destruction of autoimmune tolerance and abnormal activation of the immune system, in which Tregs dysfunction plays a key role [4].
Normal human liver tissue contains a small amount of fat, such as triglycerides, phospholipids, glycolipids and cholesterol, and its weight is about 3% to 5% of liver weight. If the intrahepatic fat exceeds 5% of the liver weight or more than 50% of histologically hepatocytes have steatosis, it can be called fatty liver.
The common causes of the disease include alcoholism, rapid weight loss, malnutrition, and diabetes.
Viral hepatitis is a disease caused by many different hepatitis viruses, and it is a highly contagious epidemic.
According to the difference in the virus causing hepatitis, hepatitis can be divided into five types: hepatitis A, B, C, D, and E (HA, HB, HC, HD, HE). They are caused by five viruses respectively: HAV, HBV, HCV, HDV and HEV.
Among the 5 viral hepatitis, viral hepatitis A and E mainly manifest as acute hepatitis. Viral hepatitis B, C, and D may be manifested as acute hepatitis or chronic hepatitis, and may develop into cirrhosis and hepatocellular carcinoma. In addition to these five viruses, there are also hepatitis F virus and hepatitis G virus.
Hepatitis A (HA) is caused by hepatitis A virus (HAV). HAV belongs to the family of picornaviruses, a genus of hrpstovirus. In 1973 [5], it was found in the feces of patients with acute HA. The HAV genome consists of a single strand of linear RNA and is approximately 7.5 kb in length. From the difference in nucleic acid sequence, it can be divided into 7 genotypes [6].
HBV is a DNA virus, and HBV is a family of Hepadnavirus, which basically binds only to liver cells. It is a virus that causes hepatitis B virus disease. The HBV genome is approximately 3.2 kb and can be divided into 8 genotypes [7]. The virus was discovered by Dana in 1965. The mature virus particles are 42 nm spherical particles and are therefore also known as Dane particles.
Figure 2 Hepatitis B virus particles
HCV is an enveloped RNA virus, belonging to the flavivirus genus. Its genome is 9.4Kb of single-stranded positive RNA, which is easy to mutate. It can be divided into 6 genotypes and different subtypes. It is a virus that causes hepatitis C. The virus was first cloned from infected sera in 1959 by molecular cloning techniques.
The virus can cause hepatitis D. The virus was discovered by Rizzetto et al [8] in 1977 using direct immunofluorescence to detect liver tissue in chronic HBsAg carriers.
HDV is an HBV-dependent RNA-deficient virus and is now classified as the Satellite Virus (Satellites) family. Its replication, expression of antigen require the assistance of HBV or other hepadnavirus. HDV usually co-infection with HBV. HDV is often superinfeciton with HBV.
HEV is a single-stranded positive-strand RNA virus that causes hepatitis E. The virus is still an unclassified virus. The HEVs prevalent in the world belong to the same serotype, but according to their cDNA sequence differences, they can be divided into two subtypes: Mexican strain (M strain) and Burmese strain (B strain), and the nucleotide homology of the two is 75%.
Different viral hepatitis, its transmission route also has some differences.
Hepatitis A: HAV is mainly transmitted through the fecal-oral route, often with outbreaks or epidemics.
Clinical manifestations are chills, fever, nausea, fatigue, loss of appetite, hepatomegaly, abnormal liver function, black urine and jaundice.
Hepatitis B: HBV can cause both acute and chronic infections. HBV transmission mainly includes:
Iatrogenic transmission: Iatrogenic transmission is mainly caused by blood transfusions and blood products, or medical devices and other items contaminated by blood and body fluids of patients. It is one of the important routes of transmission of hepatitis B.
Mother-to-child transmission: It is the worldwide route of transmission of hepatitis B. The route of mother-to-child transmission of HBV is intrauterine infection, intrapartum infection and postpartum infection.
Sexual contact: HBV can be detected in the saliva, semen, menstrual blood and vaginal secretions of HBV carriers. Therefore, hepatitis B virus can be transmitted to each other through kissing and sexual intercourse.
Figure 3 Transmission of hepatitis B infection
Hepatitis C: Blood transmission is the main mode of transmission of hepatitis C virus. Its transmission is mainly based on blood transfusion [9], blood products and injection [10]. In addition, hepatitis C virus can also be transmitted vertically through mother and child.
Hepatitis D: It is mainly transmitted through blood and body fluids.
Hepatitis E: The source and route of transmission of hepatitis E (HEV) is similar to that of hepatitis A.
The liver damage caused by viral hepatitis is not directly caused by the hepatitis virus to liver cells, but mainly related to the autoimmune response.
In the case of hepatitis B, for example, the virus does not directly damage liver cells, but causes liver tissue damage through an immune response.
Under normal immune conditions, hepatitis B virus stimulates the immune system to produce sensitized lymphocytes and specific antibodies, all of which attack the liver cells with the virus, causing the liver cells to rupture, degeneration and necrosis while removing the virus. If liver cell necrosis is severe, leading to fibrous hyperplasia, the disease may change to cirrhosis.
Infants with incomplete autoimmune system and adults with low immunity, when stimulated by HBV, the immune system of the human body cannot produce antibodies normally and is in the state of immune tolerance. Due to the inability to clear HBV, it has long been a chronic hepatitis B carrier and is prone to cirrhosis and liver cancer.
Studies have shown that after HBV infects the body, immune cells of T lymphocytes in the body accumulate or over-activate in liver tissues, resulting in impaired liver function [11]. When the immune response function is too strong, excessive reaction will lead to apoptosis of infected liver cells, and liver function will be damaged, causing severe hepatitis. The variant hepatocytes produced by hepatitis stimulation gradually accumulate into liver cancer.
Figure 4 Symptoms of hepatitis
For hepatitis, you can find information about the liver by examining the following items: Liver function (serum ALT, AST, total bilirubin, direct bilirubin, indirect bilirubin, albumin, globulin, cholinesterase, alkaline phosphatase, transpeptidase, etc.), ultrasonography, abdominal enhanced CT or MRI, liver biopsy.
Anti-HAV: IgM occurs earlier and is usually detected in the blood at the onset of clinical symptoms. Detection of anti-HAV IgM is the most common method for diagnosing acute HAV infection. At present, serum anti-HAV IgM is mainly detected by enzyme-linked immunosorbent assay (ELISA) as a specific indicator for early diagnosis of hepatitis A [12].
HAV RNA detection: The presence of hepatitis A virus nucleic acid is determined by amplification and detection of highly conserved specific ribonucleic acid sequences in the hepatitis A virus gene [13].
Immunological test: The diagnosis of hepatitis B virus mainly depends on the determination of three pairs of antigen-antibody systems: Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B e antigen (HBeAg), Hepatitis B e antibody (HBeAb), Hepatitis B core antigen (HBcAg), Hepatitis B antibody (HBcAb).
HBsAg is the main component of the outer membrane of the virus and can be present in the blood of infected people. It is the main marker of HBV infection and the main component of vaccine preparation. HBsAg positivity usually means the presence of HBV infection.
HBsAb is a protective antibody whose presence indicates immunity to hepatitis B.
HBeAg is a nuclear protein secreted into the blood, HBeAg positivity indicates that the virus replication in the liver is active and highly contagious.
HBeAb indicates termination of viral replication or only low replication, infectivity disappears or is less contagious.
HBV DNA detection: There is a mutation in HBV, and HBsAg may not be detected in the serum of patients infected with the mutant strain, and HBV DNA can be detected at this time. With the continuous development of medical science and technology, the application of HBV DNA detection in the diagnosis of hepatitis B has become more and more popular [14] [15].
Other hepatitis virus like hepatitis C and hepatitis D, which are detected by anti-HCV antibody, HCV RNA and anti-HDV antibody, HDV RNA.
Vaccination is the most effective way to prevent various hepatitis. The vaccine used is different for different hepatitis viruses.
Vaccines against hepatitis A virus are mainly divided into two categories: live attenuated hepatitis A vaccine and inactivated hepatitis A vaccine. In addition, recombinant genetic engineering vaccines have also made great breakthroughs. Studies have shown that it is feasible to prepare HAV genetically engineered vaccines by genetic engineering methods.
Hepatitis B vaccines mainly include blood-derived vaccines and genetically engineered vaccines. In addition, some HBV mutant strains can escape the current HB vaccine immunization. Therefore, the development of vaccines against HBV mutant strains is one of the important topics in HB research today.
Since HDV infection requires HBV assistance, HB vaccine can also be used for pre-exposure prophylaxis of HDV.
The vaccine against hepatitis E is a genetically engineered vaccine.
The treatment of viral hepatitis generally includes: anti-hepatitis virus, improving liver function, and enhancing immune regulation.
Immunomodulators, mainly including interferons.
Antiviral drugs: Currently, first-line treatments include entecavir and tenofovir, while lamivudine and adefovir are not used as first-line treatments due to high drug resistance and nephrotoxicity.
The combination of antiviral drugs and vaccines can greatly improve the prevention and treatment of viral hepatitis.
In addition, RNA interference (RNAi) has been recognized as the future direction of treatment for severe HAV infection.
Liver transplantation is a serious way of treatment when viral hepatitis is severe.
References
[1] Bynum T E, Boitnott J K, Maddrey W C. Ischemic hepatitis [J]. Digestive Diseases and Sciences, 1979, 24(2): 129-135.
[2] Tapper E B, Sengupta N, Bonder A. The Incidence and Outcomes of Ischemic Hepatitis: A Systematic Review with Meta-Analysis [J]. The American Journal of Medicine, 2015, 128(12): S000293431500769X.
[3] Moy L, Levine J. Autoimmune Hepatitis: A Classic Autoimmune Liver Disease [J]. Current Problems in Pediatric and Adolescent Health Care, 2014, 44(11): 341-346.
[4] Herkel, Johannes. Regulatory T Cells in Hepatic Immune Tolerance and Autoimmune Liver Diseases [J]. Digestive Diseases, 2015, 33(2): 70-74.
[5] Feinstone S M, Kapikian A Z, Purcell R H. Hepatitis A: Detection by Immune Electron Microscopy of a Viruslike Antigen Associated with Acute Illness [J]. Science, 1973, 182(4116): 1026-1028.
[6] Yokosuka O. Molecular biology of hepatitis A virus: significance of various substitutions in the hepatitis A virus genome [J]. J Gastroenterol Hepatol, 2000, 15.
[7] Locarnini S. Molecular virology of hepatitis B virus [C]. Seminars in Liver Disease, 2004.
[8] Rizzetto M, Canese M G, Arico S, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers [J]. Gut, 1977, 18(12): 997-1003.
[9] Marcellin P, Martinot-Peignoux, Michèle B N, et al. Second generation (RIBA) test in diagnosis of chronic hepatitis C [J]. Lancet, 1991, 337(8740): 551-552.
[10] Galeazzi B, Tufano A, Barbierato E, et al. Hepatitis C virus infection in Italian intravenous drug users: epidemiological and clinical aspects [J]. Liver International, 1995, 15(4): 209-212.
[11] Kaffenberger B, Haverkos B, Tyler K, et al. Extranodal Marginal Zone Lymphoma-like Presentations of Angioimmunoblastic T-Cell Lymphoma: A T-Cell Lymphoma Masquerading as a B-Cell Lymphoproliferative Disorder [J]. The American Journal of Dermatopathology, 2015, 37(8): 604-13.
[12] H. Poznańska. Laboratory diagnosis of viral hepatitis [J]. Infectious Disease Clinics of North America, 2001, 15(4): 1109-1126.
[14] Kohmoto M, Enomoto M, Yano Y, et al. Detection of serum hepatitis B virus DNA by real-time quantitative polymerase chain reaction (TaqMan PCR) during lamivudine treatment: comparison with three other assays [J]. Hepatology Research, 2003, 26(2): 125-133.
[15] Aliyu S H, Aliyu M H, Salihu H M, et al. Rapid detection and quantitation of hepatitis B virus DNA by real-time PCR using a new fluorescent (FRET) detection system [J]. Journal of Clinical Virology, 2004, 30(2): 0-195.
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