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Hepatitis C Hepatitis C is a hepatic disease caused by virus called hepatitis C virus(HCV). This disease was initially named non-A,non-B(NANB) hepatitis after ruling out hepatitis A,hepatitis B and a variety of other viral and bacterial infection. despite of intensive efforts and untiring investigations, the virologists could not determine the etiological agent of this disease. Various type of virus particles were found present in the serum, urine, hepatocytes and KUPPER CELLS but virologists failed to establish etological relationship with NANB hepatitis. A few workers persistently observed the association of a virus with majority of the cases of NANB hepatitis. This virus eventually attracted the attention of virologist who cloned it in three different laboratories by recombinant DNA techniques. the clones were thoroughly studied and found similar in all respect. the virus was then named hepatitis C virus and the disease hepatitis C.In 1989, a serological test was developed to detect antibodies specific to HCV. The test proved highly useful in the serological diagnosis of acute and chronic hepatitis c.the repeated application of this test yielded results that confirmed the involvement of HCV in cases of NANB hepatitis. VIRAL STRUCTURE HCV is a spherical, enveloped, single-stranded RNA virus included in the family Flaviviridae. The diameter of the virus is approximately 50nm.The structure of the envelop is covered with the protein spikes. The RNA is a linear structure comprising of 9379 nucleotides. It acts as genome of the virus. The 5'terminal of the genome encodes the structural capsid and envelop proteins. The 3'terminal on the other hand,is the functional region and thus encodes viral proteases, RNA polymerase, and regulatory proteins. The RNA genome is a positive strand which encodes for a polyprotein of 3010 to 3030 amino acids. This protein undergoes proteolytic post-translational cleavage. The capsid is composed of phosphorylated protein. The diameter of the virus is approximately 50nm.The structure of the envelop is covered with the protein spikes. The RNA is a linear structure comprising of 9379 nucleotides. HOW VIRUS REPLICATE? HCV replicated in the cytoplasm of hepatocytes. Following penetration, the positive RNA strand is first translated to synthesize various structural proteins including RNA_dependent RNA polymerase. The RNA polymerase prepares a complementary copy, or the negative strand, using the positive strand as a template. The negative strand act as a replicative intermediate. The RNA_dependent RNA polymerase uses this structure as template and synthesize positive strands.

The virus is then assembled that is released by a process of budding. GENETIC VARIATION IN HCV HCV has a tendency to undergo genetic variation during the process of replication. This tendency has been related to the lack of proofreading mechanism for the newly synthesized RNA. Thus, HCV populations are extremely heterogenous. This persistent diversity over the centuries has led to the development of several distinct groups of the virus and now classified as six major HCV subtypes. It is yet to be confirmed what role these genotypes or their subtypes play in the severity of the disease. The ability of HCV to change its genotype character over time also occurs within the infected person and creates a family of closely related viruses with minor differences ,called quasispecies.These minor changes do favor the virus by providing it an ability to escape the host's immune surveillance .It is because the antibody produced against one quasispecies often fails to defend against another quasispecies PATHOGENESIS Hepatitis C is a worldwide disease involving all segments of population. HCV is present in the blood of the patients and carriers. It is established that about to infectious doses may be present in one microliter of the blood .Till a couple of years back, the transmission was believed to occur through transfusion of blood with sharing of needles and promiscuous sexual activities as other risk factors. The transmission patterns have, however, changed in recent years. Although direct percutaneous exposure through transfusion of blood products remains an efficient means of transmission, currently most HCV infections are acquired outside the transfusion settings. Modern blood bank practices, including the blood screening tests for viral diseases have nearly eliminated the risk of HCV infection for the blood recipient in most part of the planet. As a consequence, injection-drug use has emerged the most common cause of HCV infection. According to one medical survey, more than 75% of all new injection-drug users become seropositive for HCV within one year after beginning drug use. In Pakistan, the situation, however remains the same, as the transfusion practices are not safe as in many other countries. Hence, the blood transfusion remains the main cause of HCV transmission. Today,the most commonly identified risk factors are injection-drug use,hemodialysis, sexual or household exposure to an infected contact,multiple sexual contacts or perinatal exposure and health care employment. Low socioeconomic status also remains an important risk factor for HCV infection .Transmission of HCV to the host is the beginning of the infection .The virus is transported to the liver via blood circulation where it initiates the process of replication in hepatocytes. CLINICAL MANIFESTATIONS The clinical manifestation of Hepatitis are similar to Hepatitis B. The mean incubation period of the disease is 7 weeks, with a range of 3 to 20 weeks. The disease is usually insidious in onset. It begins with anorexia, malaise, nausea, vomiting, myalgia and hepatomegaly. The disease is characterized by prolonged viremia and development of a persistent carrier state. The disease is milder than hepatitis B. The acute illness typically lasts from 2 to 20 weeks. In up to 15% of cases, the disease is self limiting; symptom resolve, HCV RNA become undetectable ,and ALT levels return to normal. Medical reports indicate that more than 85% of patients with acute disease become chronically infected (HCV RNA+) and 65% to 85% develop chronic hepatitis (elevated ALT). Among chronically infected patients, approximately 30% show a persistent normal ALT

levels whereas other have an occasional ALT elevation. The chronic hepatitis C is a progressive liver disease, characterized by some mild, intermittent, and non specific symptoms.They include fatigue, abnormal pain, fever and arthralgia.The disease progression usually evolves over decades and, in many patients may be slow that it does not result in increased morbidity or mortality. Some patients develop cirrhosis mostly during first 20 years of the disease. The symptoms exhibited by a cirrhotic patient include severe fatigue,marked muscle soreness and neuralgia,fluid retention,jaundice,darkening of urine,upper intestinal hemorrhage,and itching.In most of the cases, hepatitis C accompanied by cirrhosis may lead to hepatic failure and death. There are a few serious extrahepatic manifestations of hepatitis C. These include essential mixed cryoglobinemia (EMC),arthritis, membranoproliferative glomerulonephritis, keratoconjunctivitis and porphyria cutanea tarda .The EMC is characterized by the presence of cryoglobins in serum, hypocomplementemia ,and symptoms such as fatigue, muscular and joint pain, arthritis ,dermatitis, and neuropathy. LABORATORY DIAGNOSIS

ELISE-2: Hepatitis C is diagnosed in the laboratories by serological methods. The most important method for detecting antibodies specific to HCV is the second generation enzyme-linked immunoassay (ELISA-2).The test is gaining popularity nowadays as it is simple, automated, easily reproducible, and extremely high, more than 90% and only one positive test is reliably sufficient for diagnosis. Attempts are being made to develop a third-generation assay with the sensitivity and specificity higher than 95%.

RECOMBINANT IMMUNOBLOT ASSAY (RIBA) This test is based on the use of recombinant viral antigen, named C100-3,in a capture Assay for circulating HCV antibodies.Anti-C100-3antibodies appear to be developed against nonstructural viral epitopes weeks or months after acute infection. The presence of anti-C100-3 antibodies is also indicative of chronic persistent viremia.

HCV RNA ASSAY A recent approach in the diagnosis of hepatitis C is based on the demonstration of HCV RNA in the blood of the patient. This method is called HCV RNA ASSAY is considered very useful in the detection of HCV genome and measurement of the level of circulating virus in the infected person. The test is also useful in the monitoring the effectiveness of antiviral therapy. THERAPY Currently, interferons are the only agents with proven efficacy in the treatment of hepatitis C.Three types of interferons are now available in the market: Interferon alpha-2b(marketed in 1991),Interferon alpha-2a(marketed in 1996) and a synthetic consensus interferon alpha con1(marketed in 1997).Other interferons under investigation, a lymphoblastoid interferon and interferon beta PREVENTION

Measures as recommended by WHO to prevent hepatitis C are same as those for Hepatitis B. There is, however, no vaccine available so far .The main problem in developing an effective vaccine for HCV infection is genetic variation the virus persistently exhibits in its genome. It is however, recommended that all patients with hepatitis C should be vaccinated against hepatitis A and hepatitis B as these infections may cause significant morbidity and mortality when superimposed on pre-existing disease.

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