Hepatitis
Summary/Definition
The hepatitis B is a pathological condition caused by exposure to the hepatitis B virus. The hepatitis B virus can provoke the development of both acute and chronic hepatitis. The Republic of Korea has a high prevalence rate of chronic hepatitis B. Patients with chronic hepatitis B have a high risk of developing liver cirrhosis (cirrhosis) or liver cancer (hepatocellular carcinoma), so the diagnosis and treatment of chronic hepatitis B are very important.
Hepatitis C is a disease caused by infection with the hepatitis C virus. Like hepatitis B, it is divided into acute and chronic hepatitis. In most adults, acute hepatitis C becomes chronic. At the initial stages of the development of this disease, symptoms are usually absent, so early diagnosis through a medical examination is critically important.
Viral hepatitis is a disease in which inflammation of the liver tissue occurs and a variety of clinical manifestations are caused by a viral infection.
Acute viral hepatitis is called viral hepatitis, which is cured within 6 months from the moment of occurrence, and if the infection persists for more than 6 months, it turns into a chronic form.
Causes of viral hepatitis and transmission routes
The main causative agents of viral hepatitis are hepatitis A, B, C, D, and E. Hepatitis B and C can pass from the acute phase to the chronic, while hepatitis A and E do not have this ability and remain in the acute phase without transitioning to the chronic form.
Table 1. Causes of viral hepatitis
| Section | Hepatitis А | Hepatitis B | Hepatitis C | Hepatitis D | Hepatitis E |
| Clinical endpoint | Acute | Acute/chronic 5-10% of adults with acute hepatitis develop chronic hepatitis. | Acute/chronic Most adults with acute hepatitis develop chronic hepatitis. | Acute/chronic | Acute |
| Transmission route | Feces, oral cavity | Parenterally, sexually, or through infected blood or body fluids | Parenterally, sexually, or through infected blood or body fluids | Parenterally | Feces, oral cavity |
| Recommended treatment method | There is no specific treatment method. | Oral antiviral drug interferon | Complex therapy with the oral antiviral drugs interferon and ribavirin | There is no specific treatment method. | |
| Remark | Symptoms similar to the flu, for example, fever, muscle pain, jaundice, etc. |
1. Transmission routes of hepatitis B
The hepatitis B is transmitted by contact with infected blood, sexual contact with an infected person, or by transmission from mother to child during childbirth (regardless of their nature, whether natural childbirth or cesarean section). Currently, the following transmission routes for hepatitis B have been established: blood, semen, and saliva. Transmission through feces, urine, or sweat has not been proven. The probability of infection is considered high if the blood of an infected person gets into a wound on the skin, inside the mouth or vagina of a healthy person, as well as if a healthy person is pricked with a needle containing the carrier’s blood. Infection can also occur sexually or by sharing a toothbrush or razor. However, people who have antibodies to the hepatitis B virus are not at risk of infection.
2. Transmission routes of hepatitis C
The hepatitis C virus is transmitted through the general use of syringes, blood transfusion, hemodialysis, sexual contact, and vertical transmission from mother to child. However, in approximately 40% of cases, the path of infection remains unknown.
Symptoms
The main symptoms of viral hepatitis include nonspecific manifestations such as fatigue, drowsiness, and loss of appetite, as well as such characteristic symptoms of hepatitis as dark brown urine, jaundice (yellowing of the whites of the eyes and skin), and pain in the right upper abdomen.
Symptoms of chronic viral hepatitis can range from asymptomatic infection to end-stage liver failure. In most patients who develop chronic hepatitis, symptoms appear gradually.
1. Common symptoms of chronic hepatitis
The symptoms of chronic viral hepatitis range from asymptomatic infection to end-stage liver failure. At the initial stages of chronic hepatitis, most patients do not have characteristic symptoms, and clinical symptoms develop gradually as the disease progresses. However, the most common symptom associated with hepatitis is chronic fatigue. As chronic hepatitis progresses, periodic or permanent manifestations of jaundice may occur, as well as complaints of loss of appetite, nausea, and vomiting.
2. Symptoms associated with complications of chronic hepatitis
1) Symptoms of cirrhosis of the liver
Jaundice, a characteristic sign of cirrhosis of the liver, is accompanied by a change in the color of urine to dark brown and yellowing of the whites of the eyes and skin. At the ascites stage, bloating is observed, which may be accompanied by a deterioration in appetite. During the progression of cirrhosis of the liver, it is possible to develop dilation of the veins of the esophagus or stomach, which can cause serious bleeding in the gastrointestinal tract in patients with cirrhosis of the liver. Also, with deterioration of liver function, a hepatic coma may occur, accompanied by disorientation in time, place, and environmental conditions, and in severe cases, symptoms of clouding of consciousness.
2) Symptoms of liver cancer (hepatocellular carcinoma)
In most patients with liver cancer, the initial stages are not accompanied by specific symptoms associated with this disease, and the symptoms become noticeable only at the stage when the disease takes an advanced form. As liver cancer progresses, loss of appetite worsens, which leads to a decrease in food intake and, as a result, to weight loss. However, given that liver cancer is often accompanied by cirrhosis of the liver, ascites can cause weight gain. In the case of diagnosed progressive liver cancer with pronounced symptoms, it is difficult to expect effective treatment, and the clinical outcome is usually unfavorable. In this regard, patients who are at an increased risk of developing liver cancer against the background of chronic hepatitis should regularly undergo medical examinations for signs of liver cancer.
Diagnostics
Chronic hepatitis B is defined as a condition in which the test result for the hepatitis B virus surface antigen remains positive for a long time (more than 6 months). The surface antigen of the hepatitis B virus is detected using a blood test. This test is mandatory for the diagnosis of hepatitis B.
For the diagnosis of chronic hepatitis C, a primary screening test is used to detect antibodies to the hepatitis C virus. The presence of hepatitis C virus is confirmed by RNA analysis.
1. Diagnosis of Hepatitis B
Hepatitis B is diagnosed by a blood test, which allows you to detect the presence of hepatitis B virus surface antigen (HBsAg) in the blood. Hepatitis B can be diagnosed only with the help of this analysis. In chronic hepatitis B, a positive HBsAg test result has been observed for more than 6 months. For patients suffering from chronic hepatitis B, it is extremely important to assess the degree of viral replication. The degree of viral replication is assessed by studying the “e” antigen and antibodies to it (HBeAg / anti-HBe) and quantitative analysis of viral DNA in blood serum. Chronic hepatitis B is divided into various stages, including the stage of immune tolerance, the stage of positive immune activity against antigen “e” (HBeAg), the stage of immune inactivity and the stage of negative immune activity against antigen “e” (HBeAg), based on the level of liver enzymes, the level of virus in the blood (serum DNA of hepatitis virus B) and the results of the surface antigen test.
2. Diagnosis of hepatitis C
To check the presence of hepatitis C as a primary screening test, a test is performed to detect antibodies to the hepatitis C virus (antibodies to the hepatitis C virus). When antibodies to hepatitis C virus are detected in the blood, an additional analysis is performed for the presence of hepatitis C virus RNA to confirm the diagnosis. Even very small amounts of hepatitis C virus RNA can be detected using real-time polymerase chain reaction (real-time PCR). This method is widely used in the diagnosis of hepatitis C and evaluation of the response to therapy. If the hepatitis C virus persists in the body for more than 6 months, it can be diagnosed as chronic hepatitis C. Usually, along with an analysis of the hepatitis C virus RNA, testing for the virus genotype is also carried out, which makes it possible to predict the effectiveness of antiviral therapy.
Treatment and course of the disease
1. The course of chronic hepatitis
1) The course of chronic hepatitis B
The rate of transition from hepatitis B to a chronic form depends on the time of infection. Infection in the perinatal period leads to chronic hepatitis in 90% of cases, in childhood in 20%, and in adults in 5-10% of cases. Even after full recovery from acute hepatitis B, small amounts of hepatitis B virus can persist in the liver or blood for a long time. This condition is called a latent infection, and the hepatitis B virus can reactivate in response to immunosuppressive or anticancer therapy. Depending on the activity of the hepatitis B virus, it can be classified as active or inactive hepatitis. In the Republic of Korea, in patients with chronic hepatitis B, cirrhosis of the liver develops with a frequency of 5.1% within one year with the natural course of the disease, and the frequency of cases of cirrhosis of the liver developing within 5 years is 23% among all patients with chronic hepatitis B. It is known that liver cancer (hepatocellular carcinoma) develops with a frequency of 0.8% during the year, and the 5-year cumulative risk is approximately 3%.
2) The course of chronic hepatitis C
In approximately 50-80% of patients infected with the hepatitis C virus, the disease becomes chronic, and in this case, a natural cure becomes difficult. Chronic hepatitis C leads to long-term liver damage, which can cause liver cirrhosis and liver cancer (hepatocellular carcinoma). Among patients with chronic hepatitis C, 15-56% develop cirrhosis of the liver within 20-25 years.
Chronic hepatitis B cannot be completely cured with the use of antiviral therapy and requires prolonged treatment. Therefore, it is important to establish appropriate treatment goals and use medications with a low risk of developing resistance.
Since the elimination of the hepatitis C virus is possible with the help of antiviral therapy, all patients with hepatitis C who have no contraindications to treatment should consider the possibility of this therapy. Currently, oral antiviral drugs are widely used because they are effective and have minor side effects.
2. Treatment of acute viral hepatitis
There is no specific treatment method for acute viral hepatitis, and therapy is usually limited to the introduction of nutrients and the observance of absolute rest. Absolute rest is not required for previously healthy young patients, but in the presence of pronounced symptoms, for example, jaundice, nausea, or anorexia, rest is prescribed during injection therapy with the use of nutrients to maintain water balance in the body and nutrition. It is recommended to use a high-protein and high-calorie diet. In the case of acute hepatitis B, most adult patients recover, but in the case of acute hepatitis C, in most adult patients it becomes chronic, so regular monitoring is required to determine possible progression to chronic hepatitis.
3. Treatment of chronic hepatitis B
1) Basic principles of treatment of chronic hepatitis B
The main goal in antiviral treatment of patients with chronic hepatitis B is long-term suppression of viral replication and reduction of inflammatory processes in the liver to prevent the development of fibrosis and cirrhosis of the liver. In addition, such treatment is aimed at reducing the risk of liver cancer, reducing mortality from liver diseases, and increasing overall survival. Despite significant advances in antiviral therapy, complete removal of the hepatitis B virus from the patient’s body is currently impossible. Therefore, it is important to maintain a stable suppression of the virus to prevent its further replication.
2) Indications for the treatment of chronic hepatitis B
The decision to start treatment is determined based on several factors, including the activity of liver enzymes, the level of viral load in the blood (the amount of viral DNA in the serum) and the results of the analysis for surface antigen. If the “e” antigen (HBeAg) is positive and the level of alanine aminotransferase (ALT) remains consistently low for a long time, even with a high viral load and no signs of liver cirrhosis, treatment with antiviral drugs may not be required. Antiviral treatment is started if the virus level in the blood is high, and the ALT level exceeds the upper limit of the norm by more than 2 times. Currently, the norms of hepatitis B viral DNA levels in blood plasma are subject to changes depending on the status of the “e” antigen. In patients with chronic hepatitis B, who have an active progression of liver cirrhosis or a diagnosis of liver cancer, treatment should be started immediately, even in the absence of a significant increase in the activity of alanine aminotransferase (ALT) in the blood serum. Recommendations on treatment standards approved by the Korean Association for the Study of the Liver prescribe the following measures.
Table 2. Recommendations of the Korean Association for the Study of the Liver for the Treatment of Chronic Hepatitis B (2018 г.)
| The object of treatment | Content |
| Chronic hepatitis B, immunotolerant phase | 1. If the patient has a positive HBeAg status, a high level of hepatitis B viral DNA in blood plasma (greater than or equal to 107 IU/ml) is detected, a stable normal level of alanine aminotransferase (ALT) activity is confirmed, and no inflammation or fibrosis is detected according to the results of a liver biopsy, then antiviral treatment is not required. (B1) 2. Even if the patient has a positive HBeAg status and the activity level of alanine aminotransferase (ALT) is stable, but he has reached the age of 30-40 years, and the viral DNA of hepatitis B in the blood serum is less than 107 IU/ml, or the results of noninvasive research methods indicate clinically significant liver fibrosis, or the ALT level is approaching the upper limit of the norm, it is recommended to perform a liver biopsy to determine the need for treatment. (B2) |
| HBeAg-positive and HBeAg-negative chronic hepatitis B, immunoactive phase | 1. In the presence of HBeAg-positive hepatitis with the level of hepatitis B viral DNA in the blood serum ≥20,000 IU/ml or HBeAg-negative hepatitis with the level of hepatitis B viral DNA in the blood serum ≥2,000 IU/ml, and if the activity of alanine aminotransferase (ALT) exceeds the upper limit of the norm by more than 2 times, it is recommended to start antiviral treatment. (A1) If the ALT level is 1-2 times higher than the upper limit of the norm, then additional monitoring is carried out, or a liver biopsy is performed, and in cases of moderate or higher levels of necrotic inflammation or periportal fibrosis, antiviral treatment is prescribed. (A1) If performing a liver biopsy is difficult, then the degree of liver fibrosis can be assessed using non-invasive methods. (B1) 2. In case of a sudden increase in ALT levels 5-10 times higher than the upper limit of the norm in patients with HBeAg-positive or HBeAg-negative chronic hepatitis who are in the immunoactive phase or have experienced an acute exacerbation accompanied by liver-related symptoms, for example, jaundice, prolongation of prothrombin time, ascites and hepatic coma, it is recommended to start immediate treatment with oral antiviral drugs. (A1) 3. In the case of HBeAg-negative hepatitis with the level of hepatitis B viral DNA in the blood serum of ≥2000 IU/ml and if the ALT level is within the upper limit of normal, the treatment decision can be made based on follow-up or determination of the degree of inflammation and liver fibrosis by biopsy or the use of non-invasive methods. (B2) |
| Chronic hepatitis B, inactive carrier phase | 1. If the level of hepatitis B viral DNA in the blood serum is <2000 IU/ml, the level of alanine aminotransferase (ALT) activity is within normal limits, and patients are in the phase of inactive virus carrier without signs of progressive liver fibrosis, then treatment is not required. (B1) |
| Compensated cirrhosis of the liver | 1. In compensated cirrhosis of the liver with the level of hepatitis B viral DNA in the blood serum ≥ 2000 IU / ml, antiviral treatment should be initiated regardless of the level of activity of alanine aminotransferase (ALT). (A1) 2. In cases of compensated cirrhosis of the liver, when hepatitis B viral DNA is detected in the blood serum, antiviral treatment is considered regardless of the ALT level, even if the level of hepatitis B virus DNA in the serum is <2000 IU/ml. (B1) |
| Decompensated cirrhosis of the liver | 1. In decompensated cirrhosis of the liver, if hepatitis B viral DNA is detected in the blood serum, it is necessary to immediately begin oral antiviral therapy regardless of the level of activity of alanine aminotransferase (ALT) and consider the possibility of liver transplantation. (A1) |
| Monitoring of patients who do not need treatment | 1. If the patient does not need treatment, it is recommended to periodically monitor the level of alanine aminotransferase (ALT), hepatitis B virus DNA, and other parameters in the blood serum at intervals of 3-6 months, as well as to conduct an analysis for HBeAg / anti-HBe, etc. at intervals of 6-12 months to assess the need to start treatment. (B1) 2. In cases where it is unclear whether treatment should be started, it is recommended to regularly monitor the level of serum alanine aminotransferase (ALT), hepatitis B virus DNA, etc. at intervals of 1-3 months, to conduct an analysis for HBeAg / anti-HBe, etc. at intervals of 2-6 months, as well as to assess the degree of liver fibrosis using non-invasive methods or perform a liver biopsy to determine further treatment tactics. (B1) |
3) Medicines used for the treatment of chronic hepatitis B
For patients with chronic hepatitis B who require antiviral treatment, the possibility of treatment with oral antiviral drugs is primarily considered. Interferon injection therapy may also be considered, but its effectiveness is limited, especially in patients in the Republic of Korea with different genotypes of the hepatitis B virus, and therefore it is used less often. When choosing oral antiviral agents, it is important to consider the likelihood of developing drug resistance. In patients with chronic hepatitis B who have not previously received antiviral drugs, resistance to drugs such as entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide and besifovir occurs less frequently. Therefore, you can choose and use one of them. In patients with resistance to antiviral agents, the possibility of simultaneous administration of two antiviral drugs can be considered.
4. Treatment of chronic hepatitis C
1) General principles of treatment for chronic hepatitis C
The goal of treatment for chronic hepatitis C is to eliminate hepatitis C virus, prevent the development of liver cirrhosis, reduce the risk of liver cancer (hepatocellular carcinoma) and extrahepatic complications associated with hepatitis C virus, as well as reduce overall mortality from this disease. Antiviral treatment should be considered in all patients suffering from chronic hepatitis C, except in cases where such treatment is impractical. However, given the slow progression of chronic hepatitis C over many decades, as well as the risk-benefit ratio of antiviral therapy, active treatment is recommended only in cases where the benefits outweigh the risks.
2) Situations requiring antiviral treatment of chronic hepatitis C
The possibility of antiviral treatment should be considered for all patients with chronic hepatitis C who do not have medical contraindications. Priority in treatment is given to patients with severe liver fibrosis, patients before or after liver transplantation, as well as those who have serious extrahepatic complications caused by hepatitis C, for example, mixed globulinemia and glomerulonephritis. However, antiviral treatment is not recommended for patients with advanced somatic diseases, except in cases of chronic hepatitis C and limited life expectancy of the patient.
3) Medicines used for the treatment of chronic hepatitis C
Due to the development and introduction of oral antiviral drugs, there are significant changes in approaches to the treatment of hepatitis C. Complex therapy, including peginterferon alpha and ribavirin, which were previously widely used, is currently used in extremely limited cases, and is considered for patients with special clinical indications. Instead, oral antiviral drugs are widely used, including medications such as ledipasvir/sofosbuvir, daclatasvir, asunaprevir, ombitasvir/paritaprevir/ritonavir, dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir. The choice of a particular drug depends on various factors, for example, the patient’s condition, the genotype of the virus, and interaction with other drugs taken by the patient. The duration of treatment is also determined by the presence of cirrhosis of the liver, previously undergone liver transplantation, and a specific regimen of drug therapy.
Risk factors and prevention
The best way to prevent hepatitis B is through vaccination. It is important to note that contact with infected blood or body fluids can also increase the risk of hepatitis B infection. The hepatitis B virus is highly stable in the external environment and can survive outside the body for several days, even in dried blood samples or fluids.
There is no vaccine against hepatitis C. Therefore, avoiding contact with infected blood remains the main way to reduce the risk of infection with this virus.
1. Vaccination against hepatitis B
Vaccination against hepatitis B is a safe and effective preventive measure applicable to both adults and children. To achieve reliable protection, it is recommended to carry out triple vaccination at intervals of 0, 1 and 6 months, although a vaccination scheme with intervals of 0, 1 and 2 months is also possible. The method of vaccination at 0, 1 and 6 months is mainly used, in which the second vaccination is carried out 1 month after the first vaccination, and the third vaccination is carried out 5 months after it. If at some point compliance with this scheme is violated, vaccination can be resumed from any stage, without having to start over. In the Republic of Korea, vaccination against hepatitis B is recommended for all newborns.
Target Groups for Hepatitis B Vaccination (Virology and Medical Microbiology, 2017, 5th edition)
- All newborns
- Children, adolescents, and adults who have not been infected before or have not been vaccinated in the past
The following individuals have a high risk of hepatitis B virus infection and are recommended to be vaccinated as a priority. To do this, in the absence of information about past vaccinations or unknown immune status, it is recommended to conduct a diagnostic examination and vaccination if surface antibodies are not detected.
- Family members of patients with chronic hepatitis B
- Patients who require frequent transfusions of blood products (for example, hemophilia, aplastic anemia, leukemia, etc.)
- Patients on hemodialysis
- Injection addicts
- Employees of medical institutions
- Persons detained in penal institutions (for example, persons with disabilities, detainees, and others), as well as staff,
- Groups at high risk of contracting sexually transmitted diseases
Complications
Complications of chronic hepatitis
1) Cirrhosis of the liver and liver cancer (hepatocellular carcinoma)
Cirrhosis of the liver and hepatocellular carcinoma are serious complications of chronic hepatitis, and their occurrence depends on a variety of factors, including the characteristics of the body, and the virus, as well as social and environmental factors. Among the characteristics of the body, it is necessary to distinguish old age, male sex, the presence of a family history of liver cancer, concomitant viral infections of the hepatitis, and immunodeficiency conditions. Important viral factors are the high viral load in the blood and specific genotypes of hepatitis B virus (types C and B). It is also known that sociocultural and environmental factors play a significant role, including chronic alcohol consumption, metabolic syndrome, diabetes mellitus, obesity and smoking. In patients with progressive cirrhosis of the liver, a prolonged high viral load is accompanied by an increased risk of loss of liver function and death. It should be noted that hepatitis C causes a greater number of deaths due to chronic liver failure than liver cancer. In the USA, where the number of cases of chronic hepatitis C is high, about a third of patients with hepatitis C die from liver cancer, and, as is known, the incidence of liver cancer is about 3%.
