The role of hepatitis B virus in people with chronic liver disease
1-Pariya Hosseini,
2-Shaghayegh Yazdani*
1-Azad University, Tehran Medical BranchBachelor of Microbiology from the Department of Modern Sciences, [email protected]
2-Assistant Professor of Virology,Department of MicrobiologyFaculty of Advanced Science
&TechnologyTehran Medical Sciences, Islamic Azad University, Tehran, Iran, [email protected]
ABSTRACT
Hepatitis B is a life-threatening disease that affects the liver. Clinical manifestations of the disease range from asymptomatic to severe complications such as liver cancer and cirrhosis. Despite the availability of drugs and vaccines, the disease remains a major human health problem worldwide. Hepatitis B is highly contagious and is transmitted through contaminated blood and fluids from mother to fetus, use of infected needles, and sexual contact with an infected person. The hepatitis B virus enters hepatocytes with the help of sodium thoracolate receptor polypeptide transporter (NTCP) and multiplies in these cells, causing liver dysfunction. In fact, liver damage results from the proliferation of the virus and the activation of the immune system, especially virus-specific cytotoxic T cells. CTL and CD4Th1 cells control virus replication by killing infected cells and stimulating the production of antiviral cytokines. On the other hand, the function of these cells is very strong in people who successfully remove the virus, in contrast, in people with chronic infections, these cells are weakened. Many studies have shown that the main challenge in completely eliminating the virus is the presence of covalently closed circular DNA (cccDNA). This structure is produced in the process of the virus amplification cycle and remains inside the host cell for a long time and acts as a model for the production of pre-genomic RNA and virus replication. So far, no antiviral drug has been able to destroy this structure.
Keywords: Hepatitis B - Cirrhosis of the liver – Cytokines
Introduction
Hepatitis B virus (HBV) is one of the most important infectious diseases that has been reported in almost all countries of the world. The virus is one of the major global health problems, with carriers ranging from 0.1 to 20 percent worldwide (Lavanchy D 2004 & Lee WM 1997). Based on the prevalence of hepatitis B virus, communities are divided into 3 groups: the first group of countries with a prevalence of hepatitis B virus less than 2%, the second group of countries with a prevalence of 2% to 7%, the third group of countries with a prevalence of hepatitis Reaches above 7% have been reported (Koziel MJ et al 2010).
The virus is responsible for the deaths of about one to two million people worldwide each year (Lavanchy D., 2004), and there are an estimated 300 million hepatitis B carriers worldwide (except those unaware of their status). Has (Gulia, SP et al 2011.). In Iran, before vaccination, the rate of hepatitis B virus carriers was reported in different regions such as the second group (Montazeri GH et al. 2010), but after vaccination, the prevalence of hepatitis B virus was controlled and the rate was the same as in the first group (Alavian SM et al 2007). The hepatitis B virus causes chronic hepatitis, liver cirrhosis and liver cancer (Sosa-Jurado et al 2016). More than 200,000 people are diagnosed with cirrhosis and more than 300,000 with hepatocellular carcinoma annually.
(Gui HL et al. 2010 In Iran, 70-84% of patients with liver cirrhosis and 72% of patients with hepatocellular carcinoma have evidence of HBV) (MohamadKhani A et al. 2009).
Hepatitis B virus is one of the smallest viruses that infects humans. It belongs to the hepadena virus family, which has a relative, circular, double-stranded genome that consists of four reading frames, as shown in Figure 1-1. These frameworks encode surface (S), center (C), polymerase (P), and X genes (Kao 2011), which contain a number of proteins that are highly helpful in clinical settings, including HBsAg, HBcAg, and HBeAg. Are (Dienstag 2008).
Figure 1: HBV Reading Frameworks
Literature Review
The main features of this virus are the production of high amounts of spherical HBsAg and filamentus with a complete viral particle during propagation. Used against hepatitis B virus (BlockTM et al 2007). The virus tends to infect hepatocytes, and liver damage occurs following the stimulation of the immune system against infected cells. The virus is also known as an oncogene because it causes hepatocellular carcinoma (Locarnini S et al.
2006). The hepatitis B virus is transmitted mainly through exposure to mucosal surfaces with contaminated blood and fluids. Frequent use of non-sterile and shared needles and syringes, unprotected sexual contact is involved in the transmission of infection (MalaniPNet al2010). Accidental contact with medical needles in medical personnel, hemodialysis, ear and nose piercing, as well as contact with mucus and mucous secretions of hepatitis B carriers are other methods of transmission, although more than 30% of patients have no risk factors.
Cannot be found for transfer (Malekzadeh R et al. 2004). Acute hepatitis B in the third trimester of pregnancy is also associated with the transmission of hepatitis B virus to the baby around delivery. But most perinatal infections occur in infants born to mothers with chronic hepatitis B virus infection. Intrauterine transmission can occur but accounts for less than 2% of perinatal transmission (Shepard CW.2005. In areas with high prevalence of infection, such as Asia, mainly from mother with chronic infection to infant It is transmitted, but in areas where the prevalence of infection is low, such as Europe, the major route of transmission is through high-risk sex and injections, for example in injecting drug users (Harrison ID et al. 2013).
The normal clinical course of hepatitis B and the status of virus replication and hepatic response can be identified in five stages:
1. Immune Tolerance Stage: In this stage, the virus is multiplying, but liver enzymes are frequently normal, mainly in people under 30 years of age, who become infected at birth or in the first years of life.
2. Immune system activation stage in HBsAg and HBeAg positive patients: In this stage, the immune system is active against the virus and causes inflammation in the liver tissue, and therefore the number of transaminases increases continuously or intermittently. In people who have been infected at birth and have been in the immune system for many years, antiviral therapy is recommended to control the infection.
3. Inactive vector stage: In this stage, low virus replication and frequent transaminase levels are normal. It is necessary to measure the level of liver transaminases every 3 months for 4 consecutive times.
4. Chronic hepatitis stage with HBeAg negative: In this stage, the virus is multiplying and the amount of DNA and transaminases are alternately increased and decreased and most of these viruses have blind or pre-blind mutations to be able to make and release HBsAg. They are not and therefore this antigen is negative. Inflammation in the tissue causes garlic to liver fibrosis, and these patients have a high chance of fibrosis and liver cirrhosis. Patients need antiviral treatment at this stage.
5. HBeAg negative stage and occult virus infection: In this stage, S antigen is negative but the antibody is positive, but the virus level is less than 200 units or negative, in patients who have been treated or due to activity. The immune system of the S antigen is negative in them. These patients require antiviral therapy due to decreased immune system activity such as chemotherapy or an infected transplant (Shepard 2006).
Achieving maximum virus suppression without causing resistance to antiviral drugs, slowing the progression to cirrhosis, and reducing HCC are among the most important goals in the initial treatment of hepatitis B. Further treatment is recommended in patients whose virus has been cleared and reactivation of the virus is associated with increased serum ALT and HBV DNA levels. The goal of treatment in HBeAg-positive patients with chronic hepatitis is the loss of HBeAg to anti-HBe and the normalization of ALT levels and the maximum suppression of HBV DNA to low or invisible levels. Achieving important goals improves liver tissue, reduces disease progression and reduces the incidence of HCC, which is well seen in patients with advanced fibrosis. On the other hand, treatment is not recommended in patients who are in the immune tolerance stage or inactive carriers due to the possibility of developing treatment resistance in these patients (Liaw YF 2004). There are currently a number of medications used to treat chronic hepatitis B. One of them is recombinant interferon such as pegINF and nucleotide analogues such as lamivudine, edfovir, tolbyudine, entacavir, nefovir. Nucleotide analogues are competitive inhibitors of viral polymerase enzymes. On the other hand, they are similar in structure to the natural nucleotides used during virus replication. These analogs lack the hydroxyl group and do not form covalent bonds with adjacent nucleotides, eventually terminating the chain synthesis and stopping virus replication.
Methodology
PenINF is an immunomodulatory agent that primarily enhances innate immunity, while analogues are oral drugs and act directly by inhibiting the replication of viruses. Treatment with pegINF requires a limited time without causing resistance in the patient, but the number of patients receiving a sustained viral response is very limited.
On the other hand, treatment with oral drugs requires long-term treatment with a high chance of drug resistance.
Suppress more viruses. Today, however, second-generation nucleotide analog drugs, such as entacavir and tenfovir, both genetically inhibit resistance and are highly potent against viruses. These inhibit HBV DNA synthesis and act as a synthesis terminator (2014 GP Caviglia). Adfovir also prevents the onset of reverse transcription, and lamivudine prevents the synthesis of the negative DNA strand of the virus.
Prevention of hepatitis B infection is a public health priority, especially in people who are at high risk of becoming chronic. By educating people and correcting some behaviors, the rate of infection can be greatly reduced. All donated blood should be tested separately, and another way to reduce the risk of hepatitis B in clinical practice is to perform proper disinfection. Today, screening of pregnant women can greatly prevent the transmission of infection to infants and reduce human hepatitis B immunoglobulin to infants born to an infected mother. Vaccination is the most effective way to prevent hepatitis B infection, liver cirrhosis and hepatocellular carcinoma worldwide (Park NH 2010).
Data Analysis
For the first time, Dr. Bloomberg and colleagues in Philadelphia, USA, accidentally discovered HBsAg in the serum of a Native Australian with hemophilia. This accidental discovery sparked extensive studies that led to a
full understanding of the hepatitis B virus in later years (2004) (Malekzadeh R. In fact, hepatitis B virus is still the cause of more than 50% of acute hepatitis, 80% of cases of liver cirrhosis and About 70% of the causes of chronic hepatitis are in Iran (SheresthaMPet al 2007) Consequences of chronic hepatitis B infection include liver cirrhosis and liver cell cancer, each of which may It can cause liver dysfunction and later death in patients.
Fibrosis in the liver can progress very quickly or slowly, and in these patients, the disease can change from inactive to active, with inflammation of the liver and then fibrosis. Hepatitis B is a chronic and dynamic disease The condition of the patient with this infection can be predicted (McMahon 2009). In the human body, the immune system protects against many invaders, including parasites, fungi, bacteria and viruses. A number of factors, such as exposure to genetic mutations and exposure to radiation or chemotherapy, can weaken the immune system, which is a life-threatening factor. Lack of immune regulation can eventually lead to inflammation and autoimmunity (AKdis.2011). Genetic history can also be a factor in susceptibility to microbial diseases, which ultimately provide different immune responses.
Results
Treatment for chronic hepatitis B is still far from its true purpose. The ultimate goal of treatment is to eradicate CCC DNA in hepatocytes, which in the near future two theoretical approaches can be effective in treatment:
1. Combination therapy using nucleoside analogues and immunosuppressive drugs: By treating the level of HBV-DNA temporarily reducing and stimulating the immune system with immunostimulatory drugs that will be able to completely destroy CCC DNA virus.
2. Another method is to eradicate the virus in hepatocytes by combination therapy with nucleoside analogues. The selection of nucleosides together based on the lack of cross-reactivity in the mutation of the virus causes the CCC DNA to be destroyed.
This type of treatment is similar to the treatment of AIDS, which initially started with the low effectiveness of single drug therapy, but later developed today using a combination of drugs, thus increasing the effectiveness of treatment; Therefore, it seems that in the treatment of chronic hepatitis B, similar to what arose in the treatment of AIDS, the use of combination therapy is needed. It is hoped that more effective drugs and treatments will be very necessary in order to achieve the goals.
Discussions
The hepatitis B virus is the leading cause of hepatocellular carcinoma and liver cirrhosis, killing more than one million people a year. The range of clinical symptoms of this infection is different and leads to acute, chronic, asymptomatic infection and even lightning infection. The presence of HBsAg in the blood or serum for six months indicates a chronic infection. Age is a key factor in determining the risk of chronic infection, so that the probability of chronic infection in infants born to HBsAg-positive mothers is about 90% and in children under five years of age is 20 to 60% and infection in individuals Adults and the chance of developing a chronic infection is less than 5%. In some people, the infection is inactive and does not lead to severe liver disease, but in others it leads to fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma. One study also found that low quality of life is involved in the development of chronic diabetes. In a long-term study of untreated people with a chronic infection, the probability of the infection spreading to cirrhosis after five years from the onset of the infection is about eight to 20%, in which the probability of annual liver failure is about 20%. % And incidence of hepatocellular carcinoma is about one to 50% (MalaniPNet al 2010). In a study of 48 patients whose liver enzymes were normal for 6 months or more continuously, liver biopsies were performed and 54% showed active histology and an index above 4% in patients with normal the presence of liver enzymes does not predict liver cell damage and the patient should undergo clinical trials (Montazeri G.2005).
Various studies have shown that HBV infection is not cytotoxic in itself, and that liver damage in patients with chronic hepatitis B infection is the result of host immune system reactions against HBV. Cytokines play an important role in defense against viral infections and show their effect indirectly through the dominant host response pattern and directly by inhibiting virus replication (Khanizadeh S 2012). Also, according to the pathogenesis of hepatitis B virus, they concluded that most of the pathogenicity of this virus depends on the immunological mechanism (destruction of cells infected with cytotoxic T lymphocytes (TCC)), which in a few cases cytotoxics It has a direct effect on liver cells and the cause of chronic disease has been reported due to
weak or limited response of immune cells to viral antigens and in some cases a weakened immune system (Bortoletti F1996). In the study of hepatitis B virus genotypes, genotype D was the most widespread in the world; However, in type B, HBeAg activity is lower and compared to type C, this antigen is negative and HBeAb formation is higher. On the other hand, they found that genotype D may increase the prevalence of hepatoma and recurrence after transplantation and mortality compared to genotype A. Genotypes C and D show less response to interferon treatment than A and B, so knowledge of genotype type plays a role in choosing treatment regimen, so there is a lot of evidence to indicate the type of genotype and subgenotype. They can be effective in HBeAg negative, virus concentration, mutation pattern and clinical manifestations and even in response to treatment (Curry MP et al. 2010). The hepatitis B virus genotype has a specific geographical distribution in different parts of the world and even in one region, which is a very valuable tool for studying the transmission patterns of this virus by molecular methods. Studying the structure and functions of different HBV genotypes for each genotype makes it easier to assess the severity of the disease, its complications, response to treatment, and response to vaccine, and is more effective in controlling the disease (2005Kramvis A.). On the other hand, the clinical pathology and the result of chronic infection with hepatitis B virus are different in different genotypes. It is reported that the type of genotypes is important in their clinical outcome and such cases, such as response to treatment and garlic can be the disease pointed to chronicity (Attaran MS.et al. 2018.
Xenotype determination is a genetic marker for the genome in which genes are classified based on deletion, addition, and nucleotide replacement. This genotypic information is specific to species. Determines viral and molecular behaviors of the species and is useful in clinical outcomes (Mozhgani SH. Et al 2018).
On the other hand, the characteristics of latent infection with hepatitis B virus or OBI are HBsAg negative and the constant presence of hepatitis B virus in the liver, which is due to the low level of virus replication and cannot be detected by standard methods (Raimondo Get al 2016).
Studies show that people with chronic hepatitis have no clinical symptoms unless they enter the stage of cirrhosis or primary liver cancer (HCC), which includes symptoms such as weakness, nausea, loss of appetite, myalgia and artery allergies, and RUQ health. Pointed out (Kumar M 2009).
Conclusion
Hepatitis B infection is a major global health problem. Viral hepatitis is one of the five leading causes of premature death in the world, with at least one million people worldwide dying from viral hepatitis each year. In the last two decades of the twentieth century, with rapid scientific advances, drugs have been identified to treat them, and very effective vaccines have been discovered to prevent some of them. Studies have shown that the use of two drugs in the treatment of the disease with the aim of greater effectiveness and reducing the resistance of the virus has a good attraction, but so far has not shown a definite form. The combination of PEG IFN Alfa and lamivudine at the end of 48 weeks of treatment showed a decrease in virus concentration and had good effects. According to studies conducted by various researchers and clinicians in recent years, there are different results and opinions about the treatment of chronic hepatitis B, which despite the widespread efforts to develop drug resistance, strongly affects the treatment of patients and effective treatment. This infection has faced a great challenge in which everyone agrees as follows:
Treatment of chronic hepatitis B improves the patient overall and reduces cirrhosis and primary liver cancer (HCC).
In cases where HBeAg is negative and HBeAb is positive, treatment with oral nucleoside and nucleotide drugs should be continued until one year later.
Lambovidine reduces virus concentration and normalizes ALT, but has no effect on the virus genome integrated into liver cells (CCC DNA).
On the other hand, antiviral drugs have renal excretion. Necessary precautions should be taken in prescribing them.
