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chronic hepatitis

Liver necrosis and inflammation caused by different causes and lasting for at least 6 months

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Wang Xiaomei	(Chief physician)	Hepatology Center of Beijing Ditan Hospital
Xing Huichun	(Chief physician)	Hepatology Center of Beijing Ditan Hospital
Cheng Danying	(attending physician)	Hepatology Center of Beijing Ditan Hospital

Chronic hepatitis refers to liver necrosis and inflammation caused by different causes and lasting for at least 6 months, such as infection with hepatitis virus (hepatitis B virus, hepatitis C virus), long-term drinking, taking hepatotoxic drugs, etc. Clinically, there may be corresponding symptoms, signs and abnormal liver biochemical examination, or there may be no obvious clinical symptoms, only necrosis and inflammation of liver tissue. The course of disease is fluctuating or continuous. If proper treatment is not given, some patients may progress to cirrhosis 。

Common location: liver
Common causes: Infection with hepatitis virus, long-term drinking, taking liver toxic drugs, etc

common symptom: Mild early symptoms ， Visible nausea ， abdominal distention ， jaundice ， etc.
Western medicine name: chronic hepatitis

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Disease introduction

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Chronic hepatitis is a general term for a class of diseases. Its clinical characteristics, treatment methods and prognosis may be different due to different causes, but there are also common features: ⑴ liver function fluctuates repeatedly, and does not heal; ⑵ The liver tissue has different degrees of necrosis and fibrous connective tissue hyperplasia, showing chronic fibrosis. ⑶ The final stage of disease development is cirrhosis 。⑷ Both need liver protection and anti fibrosis treatment.

Pathogenesis and classification

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According to the etiology, chronic hepatitis can be classified as follows:

⑴ Chronic hepatitis B （chronic hepatitis B,

⑵ Chronic hepatitis C (CHC)

⑶ Autoimmune hepatitis (autoimmune hepatitis,AIH)

⑷ Chronic Alcoholic liver disease (alcoholic liver disease,ALD)

⑸ Drug induced liver disease : Drug induced liver injury (DILI)

According to the severity of the disease, chronic hepatitis can be divided into mild, moderate, severe and chronic Severe hepatitis

Pathophysiology

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The common characteristics of chronic hepatitis are: varying degrees of liver tissue necrosis and inflammation, followed by hepatic fibrosis , which can eventually develop into cirrhosis 。 At present, the assessment of the degree of chronic liver injury still mainly depends on liver biopsy, which is commonly referred to as liver biopsy. The pathological changes of chronic hepatitis can be divided into the grade of inflammatory activity and necrosis of liver tissue (G) and the stage of fibrosis (S). Inflammatory activity grade (Grade, G) is grade 4 (G1~4) G1 refers to mild activity, G2 refers to mild activity, G3 refers to moderate activity, and G4 refers to severe activity G1-2 indicates mild inflammatory activity in the liver, while G3-4 indicates severe liver necrosis; Stage, S is 4 stages (S1~4). Stage S1: fibrosis in the portal area of the hepatic lobule, with mild lesions, stage S4: cirrhosis , the lesion is serious.^[1]

Pathogenesis

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The pathogenesis of various chronic hepatitis is different, and is summarized as follows:

1) Chronic hepatitis B （CHB）： It is generally believed that HBV does not directly damage hepatocytes, but causes damage and destruction of hepatocytes through host immune response and reaction, leading to corresponding clinical manifestations. Due to different immune responses of hosts, including individual genetic and metabolic differences, the clinical manifestations and counters caused by HBV infection are also different. The immune tolerance period is basically no immune response, and the virus load in the blood is high, but basically no Liver injury 。 Immune activator is the appearance of partial immune response, Liver injury It leads to active hepatitis, and the viral load is reduced, but the immune response is incomplete, so the virus cannot be cleared. If the immune response and virus replication reach a dynamic balance, the activity of hepatitis will decrease and the viral load will decrease. If the pre-C region and basic core promoter (BCP) of the virus gene are mutated, chronic hepatitis B with negative HBeAg and positive HBV DNA will appear.

2) Chronic hepatitis C (CHC): The pathogenesis of hepatitis C is very complex. The interaction between the virus and the human immune system determines the occurrence, development and outcome of the disease.

3) Autoimmune hepatitis （AIH)： Its basic pathogenesis is that the body's tolerance to autoantigens is broken, thus stimulating the immune response to autoantigens. Immune cells attack their corresponding target antigens, causing cell apoptosis, necrosis and inflammatory reaction.

4) Chronic Alcoholic liver disease （ALD)： The occurrence and development of ALD are at least related to the following mechanisms: ① Oxidative stress: a large amount of reactive oxygen species (ROS) produced in the process of ethanol metabolism, the toxic reaction of oxygen free radicals, which causes oxidative stress in the human body Alcoholic liver disease One of the key mechanisms of occurrence and development. ② Toxic effect of acetaldehyde: acetaldehyde is an intermediate product of ethanol metabolism and one of the main factors causing chronic progressive liver damage. ③ Endotoxin: The production and absorption of intestinal endotoxin in ALD patients are increased, but the liver does not clear enough endotoxin, forming enterogenous endotoxemia, which aggravates the liver inflammatory damage through various mechanisms. ④ Toxicity of ethanol: in the process of ethanol metabolism, a large amount of NAD+is consumed, causing a series of biochemical metabolic disorders, inducing hypoglycemia and lactic acid Acidosis , causing fatty acid accumulation Fatty liver ； Ethanol also interferes with protein and nucleic acid metabolism. In addition, long-term intake of ethanol can also directly or indirectly cause innutrition 。 In a word, ALD caused by excessive drinking is the result of sequential or superposition of multiple mechanisms, which are mutually causal, inducing and promoting, forming a vicious circle.

5) Drug induced liver disease DILI： The hepatotoxicity of drugs can be divided into predictable and unpredictable hepatotoxicity; The former has a dose effect relationship and can be replicated in animal experiments; The latter is related to the specificity of the body, has no obvious dose effect relationship, is difficult to predict and is not easy to replicate in animal experiments. In clinic, DILI is mostly of the latter type. The pathogenesis of DILI is that the drug itself or its toxic metabolites directly affect the liver cells, or cause pathological changes through the immune mechanism. The immune mechanism is that drugs, as haptens, form new antigens in the body, and stimulate the responses of T cells and B cells through antigen presenting cells, leading to immune injury dominated by immune response.^[2-4]

Chronic hepatitis Disease outcome^[6]

Reversion^[6]

clinical manifestation

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Mild and moderate chronic hepatitis: the early symptoms of typical chronic hepatitis are mild and lack of specificity, fluctuating intermittently, or even without any symptoms for many years. The most common ones are fatigue and stomach discomfort, which are easy to be ignored and mistaken as stomach trouble ； Occult sex is often seen clinically cirrhosis Patient, at cirrhosis Before that, I didn't feel any obvious discomfort, nor did I have a routine physical examination, and I gradually developed into cirrhosis of the liver unconsciously; Occasionally, nausea, abdominal distension jaundice The urine color is dark, but the severity of chronic hepatitis cannot be judged according to the symptoms.

Severe and chronic chronic hepatitis Severe hepatitis : When the patient's urine color deepens, the skin and sclera yellow dye deepens, and the fatigue and appetite decline become more and more obvious, it indicates that the disease is getting worse, especially the chronic disease Severe hepatitis Occurrence of, Chronic Severe hepatitis yes hepatic failure Can be manifested as high fatigue, high abdominal distension, high jaundice And a high degree of anorexia, which can lead to hypoproteinemia, ascites, pleural effusion, abdominal infection, and decreased coagulation function, Upper gastrointestinal bleeding ， hepatic encephalopathy The clinical mortality rate is high, and active treatment is needed.^[5]

complication

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Chronic hepatitis complications are common, such as chronic hepatitis cholecystitis , hepatic diabetes , Hepatitis B related nephropathy Control the stability of liver disease and contribute to the stability of complications. On the basis of chronic hepatitis, when there are inducements, such as patients' overwork, heavy drinking, or overlapping infection with other hepatitis viruses, the disease can rapidly worsen and become chronic Severe hepatitis 。 In addition, if chronic hepatitis develops gradually, it will develop into cirrhosis. Both chronic severe hepatitis and cirrhosis develop from chronic hepatitis, which is serious and even life-threatening, but not strictly a complication of chronic hepatitis.

Diagnostic differentiation

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Supplementary Examination

Chronic hepatitis requires the following examinations:

(1) Liver function: Including serum ALT, AST, total bilirubin, direct bilirubin, indirect bilirubin, albumin, globulin, cholinesterase, alkaline phosphatase, transpeptidase, etc., to understand the degree of liver injury.

(2) Prothrombin time (PT) and PTA: PT is an important indicator reflecting the synthesis function of liver coagulation factors. PTA is a commonly used expression method of PT measurement value, which is of great value in judging disease progress and prognosis. In the near future, the progressive decrease of PTA below 40% is hepatic failure <20% is one of the important diagnostic criteria, indicating poor prognosis. There are also those who use the international standardized ratio (INR) to express this indicator, and the increase of INR value is the same as the decrease of PTA value.

(3) Hepatitis virological indicators: Five items of hepatitis B, hepatitis C antibody, understand whether there is hepatitis virus infection.

(4) Tumor markers: Such as alpha fetoprotein AFP, CA199, AFU, etc. for early detection liver cancer 。

(5) Imaging: Including abdominal liver, gallbladder and spleen color ultrasound to understand whether there is chronic liver damage and early screening liver cancer If necessary, perform abdominal enhanced CT or MRI to understand the degree of chronic liver injury.

(6) Liver transient elastic wave scanning (Fibroscan): It is a non-invasive examination that can be used to evaluate the degree of liver fibrosis in patients with chronic hepatitis. It is very important for patients with chronic hepatitis to evaluate the degree of liver fibrosis to determine the treatment plan.

(7) Liver biopsy: It is still the gold standard for evaluating the degree of liver damage in patients, including inflammatory grading and fibrosis staging.

differential diagnosis

Chronic hepatitis needs and chronic gastritis , Chronic cholecystitis identify. According to the above examination, it is not difficult to differentiate chronic hepatitis.

1) Chronic gastritis ： The symptoms are stomach distention and discomfort. The liver function was normal, and there was no chronic damage image change in the liver by color ultrasound. There was no sign of hepatitis virus infection.

2) Chronic cholecystitis ： It is manifested as discomfort in the liver area, anorexia, greasy food, etc., and the color ultrasound shows chronic cholecystitis The image of liver is normal. The liver function is usually normal and there is no sign of hepatitis virus infection; When there is gallstone When obstruction occurs jaundice Serum bilirubin, bile duct enzyme alkaline phosphatase (AKP, ALP) and transpeptidase (r-GT, GGT) increased. It often coexists with chronic hepatitis, which is a secondary manifestation of chronic hepatitis. To cover up chronic hepatitis, attention should be paid to differentiation.

Disease treatment

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The treatment of chronic hepatitis includes many aspects, such as protecting the liver, anti fibrosis, anti-virus, removing the cause of disease, and prevention liver cancer It is the most important principle in the treatment of chronic hepatitis to aim at different causes and eliminate them. Chronic hepatitis B virus carriers need regular physical examination and re examination, and usually do not need treatment.

① Liver protection treatment: There are many kinds of drugs, including glycyrrhizic acid preparations, silymarin preparations, schisandra preparations, etc.

It is applicable to all patients with chronic hepatitis.

② Anti fibrosis treatment: Most of them are oral preparations of Chinese patent medicine, which are also applicable to all patients with chronic hepatitis

③ Interferon injection antiviral treatment: Including ordinary interferon  (2a, 2b and 1b) and pegylated interferon  (2a and 2b), applicable to patients with chronic hepatitis B and chronic hepatitis C, with a course of treatment of at least one year. Interferon plus ribavirin is the standard treatment for chronic hepatitis C. The efficacy depends on the HCV genotype and the response to treatment. Those who have hepatitis C virus lower than the detection line (commonly known as negative conversion) within 4 weeks of treatment are called rapid response (RVR). This group has the best effect on interferon treatment, with a recovery rate of 87%.

④ Oral nucleoside analogue antiviral therapy: These drugs are only applicable to the treatment of hepatitis B, including Chronic hepatitis B And hepatitis B cirrhosis. In mainland China, there are four drugs as follows: lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT), entecavir (ETV); there is also a fifth drug internationally: tenofovir dipivoxil fumarate (TDF), which is used to treat patients resistant to the above four drugs. The advantage of nucleoside analogues is that they have good antiviral effect, small side effects, and easy to take. One tablet a day is widely used in clinical practice, which extends the survival period of patients with liver cirrhosis and significantly improves the quality of life of patients with liver cirrhosis. The disadvantage is that it needs to be taken for a long time, and there is a risk of drug resistance. As a special drug for the treatment of chronic hepatitis B, it must be used under the guidance of doctors, and the hepatitis B virus quantity needs to be reviewed regularly. If you stop taking drugs at will, it will promote the occurrence of hepatitis B virus resistance and lead to aggravation of the disease, even death.

⑤ Immunosuppressants: Autoimmune hepatitis In case of repeated liver function that is difficult to control by liver protection drugs, if liver puncture indicates obvious inflammatory activity in the liver, glucocorticoid or azathioprine, another immunosuppressant, should be used together to promote the recovery of the disease.

⑥ Prevention of tumor occurrence: Long history and occurrence of chronic hepatitis liver cancer The probability of cancer is increased, and the supplement of trace element selenium is helpful to enhance the anti-cancer ability; In addition, the injection of thymosin can improve the immune function and enhance the ability to prevent tumor.

⑦ Remove the cause: Abstain from alcohol and stop taking drugs that damage the liver: for Alcoholic liver disease as well as Drug induced liver disease Patients are particularly important. It is also important for chronic hepatitis caused by other reasons.

Disease prognosis

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The prognosis of chronic hepatitis varies greatly, depending on its etiology, disease progress, pathological state at the time of diagnosis and whether the treatment is timely and reasonable. Chronic hepatitis B and chronic hepatitis C can be controlled by antiviral treatment, and the replication of the virus can control the progress of the disease. Abstinence Yes Alcoholic liver disease The development of liver disease is very important. After abstinence, liver disease can be improved through active treatment. Even if continuous drinking is actively treated, the disease will continue to progress and develop into cirrhosis or even cirrhosis liver cancer 。 Autoimmune hepatitis It is easy to fluctuate and relapse, and the long-term prognosis is poor. Drug induced liver disease The prognosis is good.

Diet attention

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There is no special requirement for chronic hepatitis diet. Pay attention to balanced nutrition, eat more fresh vegetables and fruits, eat less fried food as far as possible, ban smoking and alcohol, maintain normal weight, ensure sleep time, pay attention to the combination of work and rest, and be calm. Medicines rich in vitamins and minerals, such as propolis, spirulina, fresh royal jelly, cordyceps preparations, are also helpful to improve liver nutrition and immune function.

disease prevention

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（1） Chronic hepatitis vaccine prevention

Hepatitis B can be prevented by injecting hepatitis B vaccine to produce hepatitis B surface antibody. The higher the level of hepatitis B surface antibody, the stronger the protection ability to human body. Before the injection of hepatitis B vaccine, it is necessary to check the liver function and the five items of hepatitis B. Usually, hepatitis B virus is not transmitted through the respiratory tract and digestive tract, so daily study, work or life contact, such as contact without blood exposure such as working in the same office (including sharing office supplies such as computers), shaking hands, hugging, living in the same dormitory, dining in the same restaurant and sharing toilets, will not generally infect hepatitis B virus. There is no effective vaccine to prevent hepatitis C.

（2） Strictly screen blood donors

Strictly implement the Blood Donation Law of the People's Republic of China and promote free blood donation. By detecting serum HBsAg, anti HCV, alanine aminotransferase (ALT), strictly screen blood donors to reduce blood borne transmission

（3） Prevention of transdermal and mucosal transmission

Promote safe injection. Dental instruments, endoscopes and other medical instruments should be strictly disinfected. Medical staff should wear gloves when contacting patients' blood and body fluids. For intravenous drug users psychological counseling And safety education to persuade them to abstain from drugs. Do not share razors and dental equipment, etc. Hair cutting equipment, puncture, tattoo, beauty and other equipment should be strictly disinfected.

（4） Prevention of sexual transmission

Those with a history of sexual disorder should be checked regularly to strengthen management. It is suggested that people infected with HBV and HCV should use condoms during the positive period of virus replication. Teenagers should receive correct sex education.

（5） Prevention of mother to child transmission

Pregnant women with positive HBV DNA should go to special medical institutions Mother infant block , success rate>95%; For HCV RNA positive pregnant women, amniocentesis should be avoided to shorten the delivery time as far as possible, ensure the integrity of the placenta, and reduce the chance of newborns exposed to maternal blood.

Expert opinion

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The treatment of chronic hepatitis requires doctors to comprehensively assess the degree of liver injury, etiology, possible recurrence risk of the disease, probability of cirrhosis, expected efficacy, medical costs, efficacy characteristics and toxic side effects of various drugs, patients' awareness and compliance with the disease, as well as the national medical insurance policy, and so on, so as to develop a practical treatment plan for patients. Patients should not listen to false advertisements and blindly use drugs at will. It is suggested that patients should go to a regular specialized hospital for medical treatment. During the treatment, they should not stop taking medicine at will or change the treatment plan at will, so as to avoid worsening their condition and endangering their health. Before planning to change the treatment plan, it is recommended that the patient consult with the specialist in a regular medical institution, and make a decision after receiving appropriate guidance to ensure the safety of medication.

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