Question

what is the pathophysiology of hepatitis c?

Answer 1

Belonging to the Flaviviridae family, HCV is a small enveloped virus [8]. Its genome consists of one RNA molecule that is composed of two terminal regions, 5'- and 3'- untranslated regions, and between these there is a single open reading frame that encodes a polyprotein with approximately 3000 amino acids. This polyprotein cleaves at the N-terminal side of three structural proteins, the nucleocapsid (core), envelope 1 (E1) and envelope 2 (E2), all of which are involved in the architectural organization of HCV. At the carboxyl-terminal side, the polyprotein cleaves to six nonstructural proteins, NS2, NS3, NS4 (NS4A and NS4B), NS5 (NS5A and NS5B) and NS6, which are responsible for the life cycle of the virus .

After entering a susceptible host, HCV invades, infects and replicates within the blood stream, repeating the process in various tissues, as well as in peripheral B and T lymphocytes, as it proceeds to the liver by tropism, passing through various tissues such as those of the pancreas, thyroid, adrenal glands, spleen and bone marrow . Since HCV can also directly infect the lymphatic tissue, its stimulation can lead to the development of B-cell lymphomas . It is known that the liver is the principal site of HCV replication, and various studies have shown that this virus infects approximately 10% of hepatic cells . Infection with HCV at extrahepatic sites can promote the appearance of HCV variants , thereby decreasing the chance that the immune system will recognize the virus.

To enter the host cell, HCV E2 and E1 proteins recognize and bond with the CD81 receptors present on the surface of hepatocytes and lymphocytes . Circulating HCV particles are accompanied by low-density and very low-density lipoproteins, which prompts discussion in the literature regarding the possibility that low-density lipoprotein is also a viral receptor . After the interaction of the virus envelope with the host cell membrane, HCV enters the cell through endocytosis. In the cytoplasm, the messenger RNA then undergoes translation, and polyproteins are processed; the HCV RNA then replicates, after which the new viral 'RNA's are packaged and transported to the surface of the host cell so that they can disseminate and complete a new cycle .TheHCV replication rate is high, approximately 1 × 1012virions per day; this, together with its high mutation rate, estimated at 10-3 nucleotide substitutions per year, leads to great heterogeneity in its presentations, which are known as quasispecies .The selection of and host adaptation to HCV quasispecies have given rise to distinct genotypes whose classification is based on the similarity of the sequence of nucleotides: similarity below 69% characterizes a new viral type; and similarity between 75 and 80% characterizes a subtype .

The progression of fibrosis in chronic hepatitis C has been associated with the diversity of HCV quasispecies . The production of new viruses is counterbalanced by the destruction of infected cells through tissue apoptosis or degradation in peripheral blood, since the half-life of the virus in peripheral blood is approximately 2.7 hours . Experimental studies have shown that NS3 and NS5 proteins induce apoptosis in infected hepatocytes .

In individuals infected with HCV, the persistence of the virus can be attributed the large inoculum and the high rate of viral replication, which allow the virus to evade the host immune response . There is controversy over whether the sequence of nucleotides is directly associated with more intense hepatic lesions.

There is some evidence of direct cytopathic lesion caused by HCV, including HCV-induced histological lesions with scant inflammatory infiltrate, fulminant hepatitis C after chemotherapy in liver transplants and HCV-related acute cholestatic syndrome after renal transplantation .

Studies suggest that specific genotypes, such as genotype 1, can be more cytopathic or can induce more rapid progression of the disease than do other genotypes . Genotype 1 has been shown to be the genotype most strongly associated with chronic HCV infection . The risk of cirrhosis and hepatocarcinoma has been shown to be greater in individuals presenting genotype 1b than in those presenting genotypes 2 and 3 . However, other authors have stated that HCV genotype and viral load do not influence the progression of the disease.

It is known that steatosis is a cofactor that influences the progression of fibrosis in chronic hepatitis C . Various studies have directly associated steatosis with HCV genotype 3Therefore, genotype 3 is considered cytopathic . Kumar et al. identified the reduction of steatosis as the only variable predictive of the virological response to the treatment of chronic hepatitis C in individuals infected with HCV genotype 3.