Introduction:
Viral hepatitis type C (HC)Hepatitis C), a disease caused by hepatitis C virus (HCV) infection, mainly through blood-borne transmission. Clinical manifestations include fever, gastrointestinal symptoms and abnormal liver function. Similar to hepatitis B, but lighter. Most cases are subclinical and chronic, which can lead to fulminant hepatic failure. More common in people infected with other viruses.
(1) Causes of the disease
HCV is a type of hepatitis virus that is transmitted blood. In 1989, Chiron Corporation of the United States applied molecular cloning technology to successfully clone (HCV) cDNA. HCV is the first human virus discovered using molecular biology techniques. HCV belongs to the family of togavirus, its biological traits, and its genetic structure is similar to that of flavivirus and prion. It has been confirmed that HCV is a spherical particle containing a lipid outer shell and has a diameter of 30 to 60 nm. The HCV genome is a long positive-strand, single-stranded RNA of approximately 9.5 Kb in length. The HCV genome has a large open reading frame (ORF) encoding a 3010 or 3011 amino acid polyprotein. The encoded polyprotein bodies have a distinct common structure with flaviviruses: structural proteins (including core and envelope proteins) and non-structural proteins (NS1-NS5).
HCV is an RNA virus, which is relatively easy to mutate. Only 68.1% to 91.8% of the nucleotides in different regions are identical, and can be divided into different genotypes according to the difference in HCV gene sequence. At present, there is no uniform standard and uniform method for HCV genotyping. Okamoto divides HCV into four genotypes I, II, III and IV. According to its classification, most North American and European HCV strains belong to type I. Japan is mainly type II, and there are also type III and type IV. According to Wang Yu's report in China, the northern cities are mainly type II and III, while the southern cities are more than 90% type II.
(two) pathogenesis
1. Direct pathogenic effects of HCV infection Many studies have shown that the severity of liver tissue inflammation in HCV-infected patients is associated with viremia. The correlation between the severity of liver tissue inflammation and the level of HCV RNA in hepatocytes in patients with chronic hepatitis C is more strongly correlated with serum HCV RNA levels. After treatment with interferon, serum ALT levels gradually decreased with the decrease of serum HCV RNA content. The above results suggest that HCV may have direct pathogenic effects. However, immunohistochemical studies have not fully demonstrated that the expression of HCV antigen in liver tissue is associated with inflammatory activity in liver disease. Groff and other studies have found that the presence of HCV antigen in hepatocytes does not necessarily indicate the presence of hepatocytes. HCV granules, liver disease inflammatory activity is not necessarily related to hepatocyte HCV antigen expression, and liver tissue inflammation is associated with the presence of HCV virions in hepatocytes, indicating that HCV has a direct cytopathic effect. The direct pathogenic effect of HCV may be related to the replication of HCV in hepatocytes, causing changes in the structure and function of hepatocytes, or interfering with hepatocyte degeneration and necrosis caused by protein synthesis in hepatocytes. The presence of HCV asymptomatic carriers seems to imply HCV. No direct pathogenic effects. However, most of the "chronic HCV carriers" liver tissues with normal ALTs have been reported to have different degrees of lesions and inflammation. The degree of liver tissue inflammation is related to the level of HCV replication, indicating that asymptomatic carriers are rare and further support HCV has a direct pathogenic effect.
2. Cell-mediated immune damage may be the main cause of liver disease caused by HCV. One of the important features of hepatitis C liver histopathology is the accumulation of lymphocytes in the portal area, sometimes forming lymphoid follicles. Hepatitis is obvious, and lymphocyte infiltration is undoubtedly related to immune response. Some scholars have shown that the lymphocytes infiltrated in chronic hepatitis C are mainly CD8+ cells, many of which have active epitopes, which are shown to be activated. Under the electron microscope, lymphocytes were observed to be in close contact with hepatocytes, suggesting that it is toxic to hepatocytes. In vitro tests by Mondelli et al have confirmed that cytotoxic T cells of chronic non-A, non-B hepatitis have increased toxicity to autologous hepatocytes. In chronic hepatitis C, cytotoxicity is mainly caused by T cells. In contrast, in patients with autoimmune hepatitis, immune effector cells are restricted to non-T lymphocytes. In chronic HBV infection, both non-T and T lymphocytes are involved in hepatocyte injury. HCV-specific antigens activate CD8+ and CD56+ cells, suggesting that CD56+ cells also play an important role in the pathogenesis of chronic hepatitis C. Intrahepatic T cells of patients with chronic hepatitis C can recognize multiple antigenic determinants of protein C, E1 and E2/NS1 proteins of HCV. This recognition is restricted by HLA class I and also indicates the pathogenesis of Tc cells in chronic hepatitis C. It plays a role. Other studies have shown that most of the chronic HCV-infected patients with peripheral blood and liver tissue restricted by HLA-II molecules CD4+ cells (TH-1 cells) can attack HCV-specific immune antigenic determinants, CD4+ cells to HCV core antigen The response is related to liver inflammatory activity, and TH-1 cells play a key role in chronic hepatitis C. The HCV-specific TH cell surface antigenic determinant enhances the specific response of Tc cells to HCV antigen, suggesting that TH cells can assist and enhance Tc cell attack to destroy HCV-infected hepatocytes.
The E1 and E2/NS of HCV RNA are hypervariable regions, which are easily mutated in vivo and can cause changes in the target antigen (E1, E2/NS protein) of the hepatocyte membrane of HCV-infected patients, and Tc cells will be recognized again. Emerging antigenic determinants attack and destroy liver cells, which is why the higher the HCV RNA mutation rate, the more serious the liver tissue inflammation. It also suggests that immune-mediated mechanisms play an important role in hepatocyte injury in chronic HCV-infected individuals.
3. Autoimmune HCV infection is often accompanied by the following characteristics: 1 non-specific immune disorder, such as mixed condensed globulinemia, Sjogren's syndrome and thyroiditis; 2 serum can detect non-specific autoantibodies, such as rheumatoid factor , anti-nuclear antibody and anti-smooth muscle antibody; 3 part of type II autoimmune hepatitis [anti-liver kidney microsomal type I antibody (anti-C-LKM-1 antibody) positive] may appear anti-HCV positive; 4 may appear anti-GOR 5 liver histological changes are similar to autoimmune liver disease, so it is speculated that the pathogenesis of HCV infection may involve autoimmune factors. However, the relationship between anti-HCV, anti-LKM-1 and anti-GOR, and its pathogenic significance need to be further studied.
4. Significance of apoptosis in the pathogenesis of hepatitis C Apoptosis is mediated by Fas antigen on the surface of cell membrane, and Hiramatsu et al. confirmed that Fas antigen is not expressed in normal liver tissue. When infected with HCV, Fas antigen is more common in Liver tissue with active lesions, especially around the portal area. The expression of Fas antigen in HCV-infected patients is closely related to the degree of liver tissue necrosis and inflammation, and the expression of hepatocyte HCV core antigen. This indicates that Fas-mediated apoptosis is one of the forms of HCV-infected hepatocyte death.
The pathogenesis of HCV infection is complex, and many factors and their interrelationships need further study and clarification.
Compared with other types of hepatitis, hepatitis C has its characteristic pathological changes, mainly including the following: 1 lymphocyte agglomeration in the portal area and Poulsen-Christoffersen type cholangitis (biliary epithelial cell degeneration, surrounded by a large number of lymphocytic infiltration) ) is an important feature and has diagnostic value. 2 Early cases showed sinusoidal cell infiltration, but did not affect the liver cells around the sinus is the important difference between acute hepatitis B. 3 Hepatocyte necrosis is lighter, the range is limited, and it appears later. 4 sinus and hepatocyte interstitial fibrosis is more obvious than hepatitis B, and appears earlier, which may be one of the reasons for the development of cirrhosis. 5 Hepatocyte steatosis is more common, fat vacuoles can be macrobubble or vesicular. 6 Hepatocyte eosinophilic changes are flaky and appear in the non-inflammatory response zone.
symptom:
[clinical manifestations]
1. Latent period The incubation period of this disease is 2 to 26 weeks, with an average of 7.4 weeks. Hepatitis C caused by blood products has a short incubation period of 7 to 33 days, with an average of 19 days.
2. Clinical clinical manifestations are generally lighter than hepatitis B, mostly subclinical without jaundice, common single ALT is elevated, long-term persistence does not drop or repeated fluctuations, the average ALT and serum bilirubin are lower, jaundice persists The time is short. However, there are also serious illnesses, and the clinical difficulty is different from hepatitis B.
Hepatitis C virus infection is more chronic than hepatitis B virus infection. It has been observed that about 40% to 50% develop into chronic hepatitis, 25% develop into cirrhosis, and the rest is self-limiting. Most patients with acute hepatitis C develop chronically without jaundice. The long-term fluctuation of ALT does not decrease, and serum anti-HCV continues to be high titer positive. Therefore, clinical attention should be paid to the observation of changes in ALT and anti-HCV.
Although the clinical manifestations of hepatitis C are mild, the incidence of severe hepatitis can also be seen. Five hepatitis viruses, HAV, HBV, HCV, HDV and HEV, can cause severe hepatitis, but the background and frequency of occurrence are different. Statistics from Europe and the United States indicate that the causes of acute and subacute severe hepatitis are: HBV is the most common, and Japan is mostly HCV. It is speculated that the reason may be that the HCV infection rate in Japanese population is much higher than that in Europe and America, and the HCV genotype in Europe and America is different from that in Japan. There is no detailed information in China. Most of the reports are mostly HBV. HCV-induced severe hepatitis is mostly caused by chronic hepatitis B and HCV infection. 3. Pattern of viremia A follow-up study of patients with hepatitis C after transfusion showed that HCVemia has the following patterns:
(1) Acute self-limiting hepatitis with transient viremia.
(2) Acute self-limiting hepatitis with persistent viremia.
(3) persistent viremia but no hepatitis, as a symptomatic carrier of HCV.
(4) Chronic hepatitis C with intermittent viremia.
(5) Chronic hepatitis C with persistent viremia.
4. Overlap infection of HBV and HCV Because HCV has a similar transmission route to HBV, the possibility of infecting both viruses is present, but it is more common to infect HCV on the basis of persistent HBV infection. The 302 Hospital of the People's Liberation Army found that the anti-HCV positive rate in the serum of patients with HBsAg-positive chronic liver disease was 0 (0/14) in mild chronic hepatitis (slow-moving liver); 24.24% (8/33) in chronic active hepatitis; chronic heavy Hepatitis was 33.33% (3/9). It shows that the positive rate increases with the progress and evolution of hepatitis B. It is speculated that the reason may be due to the increased chance of receiving iatrogenic infections such as blood transfusion during the progression of chronic hepatitis B. On the other hand, there are reports that there is a significant difference between the severe hepatitis with HBV/HCV overlap infection and the severe hepatitis with HBV infection alone, and the bilirubin, AST/ALT and mortality rates of the two groups. It indicated that hepatocyte necrosis in the overlapping infection group was much more serious than that in severe hepatitis with HBV infection alone.
It has been observed that HBV DNA and HCV RNA in HBV and HCV overlap cases are only 19% positive, and most of them are HCV RNA or HBV DNA single positive. In addition, almost all HCV RNA positive patients are e antigen negative cases, suggesting that the virus overlaps. The infection is proliferating and interfering.
5. HCV infection and hepatocellular carcinoma (HCC) The relationship between HCV infection and HCC has received increasing attention. From HCV infection to HCC on average for about 25 years, it can also be directly developed from chronic hepatitis without cirrhosis. The anti-HCV detection rate of HCC in different countries is different, and the initial report in China is 10.96%-59%. Due to the wide heterogeneity of HCV, the occurrence of HCC has a certain relationship with HCV infection of different genotypes. The prevalence of HCV in Japan and the United States is basically similar, but there are more HCCs associated with HCV in Japan and less in the United States. The results of the study indicate that type II HCV has the characteristics of high level of replication and poor response to interferon therapy, which may play an important role in the progressive development of liver disease and carcinogenesis, and also provide a molecular epidemic for the study of HCV-induced HCC mechanisms. Basis for learning.
The mechanism of HCV carcinogenesis is different from that of HBV. Studies have shown that HCV does not integrate into HBV DNA like HBV. It has been reported that the dual infection of HBV and HCV seems to increase the incidence of hepatocellular carcinoma, so attention should be paid to the role of HCV and HBV in carcinogenesis.
6. HCV infection and autoimmune hepatitis (AIH) Generally, autoimmune hepatitis is classified into four types according to autoantibodies, and type II AIH refers to anti-nuclear antibody-negative and anti-LKM-I-positive. Recently, the study classified type II AIH into two subtypes: type IIa AIH: young people are more common, female-dominated, have familial autoimmune diseases, immunosuppressive therapy is effective, and has nothing to do with HCV infection. Type IIb AIH: mostly elderly, male, no familial autoimmune disease, antiviral therapy is superior to immunosuppressive agents, associated with HCV infection, anti-HCV positive, anti-GOR positive, such patients should check HCV if necessary RNA.
【diagnosis】
1. The history of close contact with epidemiology (acute hepatitis patients and contaminated items) and the history of blood transfusion or blood product injection have certain reference value for diagnosis.
2. Laboratory testing
(1) Detection of serum anti-HCV by enzyme-linked immunosorbent assay (ELISA): Various anti-HCV assays have been established using various HCV recombinant proteins in vitro, and the first generation ELISA is 5-1-1 and C-100. Antigen, the second-generation ELISA increased the C22 and C33 proteins, and its sensitivity was 10% to 30% higher than that of the first generation. Generally, anti-C22 was the earliest and most common. C22 has good immunogenicity. The detection of hepatitis C after acute blood transfusion indicates that the anti-HCV is negative in the latent and acute phase, and anti-HCV is positive in the period of 2 to 52 weeks after the elevation of ALT. A third generation ELISA has been established to detect anti-HCV, which increases NS5 protein and is more sensitive than the second generation ELISA.
Due to the late appearance of IgG antibodies, even 1 year after HCV infection, it is not possible to estimate the state of viral replication. Therefore, Quiroga is equivalent to the detection of IgM anti-HCV in 1991, and has been reported since then. It is currently believed that the detection rate of IgM anti-HCV in acute hepatitis is slightly higher than that of IgG antibody (IgM anti-HCV is 64%, IgG anti-HCV is 57%). In self-limiting cases, IgM anti-HCV disappeared, but still positive in chronic cases, suggesting that IgM anti-HCV can be used as a chronic indicator, which has certain value for guiding antiviral therapy.
(2) Recombinant immunoblotting (RIBA) detection of HCV antibodies: The first generation of ELISA was established shortly. To exclude ELISA for anti-C100 false positives, Chiron provided an immunoblot test for confirmatory testing, also known as the first generation RIBA. The specificity of RIBA is higher than that of ELISA, but the sensitivity is significantly reduced. The second and third generation RIBAs have been established, and their positive rates are significantly higher than those of the first generation RIBA.
(3) Detection of HCV antigen: Krawczynski et al. extracted IgG fraction from HCV-infected chimpanzee or patient serum, labeled with fluorescein isothiocyanate as a probe, and detected HCV antigen in liver tissue by direct immunofluorescence. The authors tested four acute and three chronic hepatitis C chimpanzee liver tissues with positive HCV antigens. Blocking tests and adsorption tests have demonstrated that HCV antigens in hepatocytes are associated with viral hepatitis caused by HCV. This antigen is a specific morphological marker of HCV infection and can be used as one of the laboratory diagnostic methods for HCV infection. In addition, immunohistochemical ABC method can be used to detect HCV antigen in liver tissue.
(4) Detection of HCV RNA: HCV infection, serum virus content is extremely low, it is difficult to detect HCV RNA by conventional molecular hybridization technology, PCR technology is currently the most sensitive detection technology in the field of molecular biology, has been used Detection of HCV RNA. This method is the most reliable indicator for determining whether or not HCV infection is contagious. It has good specificity and high sensitivity, which is conducive to the early diagnosis and evaluation of HCV infection. However, attention should also be paid to the possibility of false positives due to high sensitivity, complicated operation, and contamination.
3. Liver biopsy light microscopy and electron microscopy have certain reference value.
diagnosis:
The disease should be associated with elevated levels of serum transaminases or serum bilirubin caused by toxic hepatitis, cholecystitis, infectious mononucleosis, leptospirosis, epidemic hemorrhagic fever, fatty liver, and amoebic liver disease. Identification. Cholestatic hepatitis should be differentiated from extrahepatic obstructive jaundice (such as pancreatic head cancer, cholelithiasis, etc.).
complication:
Common complications include arthritis (12% to 27%), glomerulonephritis (26.5%), and nodular polyarteritis. Direct immunofluorescence and electron microscopy were used to find HBV particles on the joint synovium. In patients with membranous glomerulonephritis with persistent HBsAg, HBcAg deposition was found in renal biopsy glomerular tissue. In this hospital, 180 patients with glomerulonephritis were examined by renal puncture, and 33 patients (18.3%) with HBcAg deposition in the kidney were found. Immune complex deposition of HBcAg, IgG, IgM, C3, etc. can be seen on the vessel wall of patients with nodular polyarteritis. Uncommon complications include diabetes, fatty liver, aplastic anemia, polyneuritis, pleurisy, myocarditis, and pericarditis. Among them, diabetes and fatty liver are worthy of attention. A small number of patients can have hyperbilirubinemia after hepatitis.
treatment:
(a) treatment
1. Interferon (IFN) treatment of IFN in the treatment of chronic hepatitis C after transfusion is 25%, can prevent 30% of acute hepatitis C to chronic development, so far, IFN is still recognized as a treatment of type C Hepatitis virus drugs.
Omata reported that ALT returned to normal after one year of transfusion of hepatitis C, 64% in the IFN-treated group, 7% in the control group, and 90% in the HCV RNA-negative group after transfusion, 90% in the IFN-treated group and 0% in the control group. It is generally believed that the shorter the HCV infection time, the lighter the liver histological lesions, and the lower the viral level in the blood, the better the curative effect. Therefore, for acute hepatitis C, blood ALT does not decline, should consider IFN antiviral treatment. Patients with chronic hepatitis C, with the following indicators, can also be treated with IFN: 1 serum ALT persists abnormally; 2 liver histology has chronic hepatitis characteristics; 3 has a history of injecting drugs or engaged in medical workers; Caused by liver disease, especially autoimmune liver disease; 5HCV serum index is positive.
The IFN dose is currently generally 3 to 5 mV, 3 times a week for 6 months. It has been reported that during the interferon treatment, more than 50% of patients with chronic hepatitis C have improved biochemical and histological indicators, but some patients relapse within 6 to 12 months. However, if the patient continues to be normal at 12 months after treatment and serum HCV RNA is negative, it may be cured. Extending the treatment can increase the response rate.
Factors affecting the efficacy of IFN, in addition to age and duration of disease, are mainly related to the following factors: 1 genotype: gene type II IFN treatment is poor, type III treatment is good; 2 serum HCV RNA content: generally considered, patient initial HCV RNA drop Degree is highly correlated with IFN efficacy. The initial titer of HCV RNA is low, and IFN treatment is effective; 3 virus variation: The theory of IFN sensitivity and tolerance to HCV has been proposed. Enomoto et al analyzed the full-length HCV gene sequence and amino acid sequence of each HCV-1b-infected patient, and found that the patient's response to IFN treatment was related to the change of HCV-1b quasispecies. One of the patients had two HCV quasispecies before IFN treatment, one disappeared from the patient shortly after IFN treatment, and the other quasispecies were throughout. There was no change during IFN treatment. When the difference between the two quasispecies sequences was compared, it was found that a mutation occurred mainly between the codon sequences of the hydroxyl terminus of the HCVNS5A protein (2209-2248). This region is referred to as the "IFN Sensitivity Determination Region (ISDR)", and it is considered that all of the quasispecies with the prototype HCV-1b are resistant to IFN-, while the HCV-1b quasispecies with the ISDR mutant are sensitive to IFN. The latter IFN efficacy was significantly higher than the former. 2. Ribavirin (Virazole, Ribavirin) Most scholars at home and abroad believe that ribavirin in the treatment of chronic hepatitis C, showing a certain effect in improving liver function and anti-virus, but this effect stops It can not be maintained after the drug, and can be used together with IFN or an immunomodulator to improve the therapeutic effect.
3. Liver transplantation Chronic hepatitis C can be treated with liver transplantation. However, HCV infection often occurs in newly transplanted liver, which is caused by the introduction of extrahepatic HCV, and acute severe hepatitis can also occur.
(two) prognosis
Hepatitis C virus infection is more chronic than hepatitis B virus infection, and about half of cases of acute hepatitis C have evolved into chronic hepatitis C. Follow-up observation of acute hepatitis C for 5 years, liver pathological examination confirmed that 60% developed cirrhosis. Japanese and Western data indicate that 70% of post-hepatitis cirrhosis is caused by HCV infection. The prevalence of hepatitis B in China is very serious, so hepatitis cirrhosis caused by HBV infection is still present. On the basis of cirrhosis, it can be converted into hepatocellular carcinoma. The incidence of cirrhosis after HCV infection is higher than that after cirrhosis after HBV infection. It usually takes about 20 to 25 years from hepatitis C to hepatocellular carcinoma.
prevention:
1. Anti-HCV screening of blood donors is an important measure to reduce hepatitis C after transfusion.
2. Manage the source of infection
According to the type of hepatitis patients, use disposable medical supplies; publicize the knowledge of prevention and treatment of hepatitis C, and abide by the disinfection and isolation system.
3. Cut off the route of transmission
The medical device is disinfected by one use, and the disposable medical supplies are used; the indications of blood transfusion, plasma and blood products are strictly controlled; the quality of blood and blood products is guaranteed.
4. Protect susceptible populations
It has been reported that immunoglobulin is effective in preventing hepatitis C, and its usage is 0.06 ml/kg, which is intramuscularly injected. The ultimate control of this disease depends on vaccine prevention, and the successful cloning of HCV molecules provides conditions for vaccine prevention for this disease.
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