hepatitis c presentation

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If a screening test shows hepatitis C, other blood tests can:

• Measure the quantity of the hepatitis C virus in the blood, called the viral load.
• Show the genotype of the virus.

Tests for liver damage

One or more of the following tests looks for liver damage in chronic hepatitis C.

• Magnetic resonance elastography (MRE). This noninvasive imaging can be done instead of a liver biopsy. It mixes magnetic resonance imaging technology with patterns formed by sound waves bouncing off the liver. This makes a map that shows places where the liver is stiff. Stiff liver tissue means scarring of the liver, called fibrosis.
• Transient elastography. Another test of liver stiffness is a type of ultrasound that sends vibrations into the liver. The test measures how fast the vibrations go through liver tissue.
• Liver biopsy. This is often done using ultrasound as a guide. It involves putting a thin needle into the liver to remove a small sample of liver tissue to be tested in a lab.
• Blood tests. A series of blood tests can show the amount of scarring in the liver.

A member of the care team does transient elastography to find liver damage. This sometimes can be done instead of a liver biopsy.

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Antiviral medicines

Antiviral medicines treat hepatitis C. They're used to clear the virus from the body. The goal of treatment is to have no hepatitis C virus found in the body for at least 12 weeks after treatment ends.

Some newer antiviral medicines, called direct-acting, have better outcomes, fewer side effects and shorter treatment times. Treatment can be as short as eight weeks. The choice of medicines and length of treatment depend on the hepatitis C genotype, whether the liver is damaged, other medical conditions and earlier treatments.

Throughout treatment, the care team watches the treatment for response to the medicines and side effects. Treatment with direct-acting antiviral medicines usually lasts 12 weeks.

Due to the pace of research, treatments are changing quickly. So it's best to discuss treatment choices with a specialist.

Liver transplantation

Having a liver transplant might be an option for serious liver damage from chronic hepatitis C infection. During a liver transplant, a surgeon removes the damaged liver and replaces it with a healthy liver. Most transplanted livers come from dead donors. A small number come from living donors who donate a part of their livers.

In most cases, a liver transplant alone doesn't cure hepatitis C. The infection is likely to return. This means more treatment with antiviral medicines to prevent damage to the new liver. Several studies have shown that newer antiviral medicines cure hepatitis C after a transplant. Sometimes, the newer antivirals can cure hepatitis C before a liver transplant.

Vaccinations

There's no vaccine for hepatitis C. But a health care provider will likely recommend vaccines against the hepatitis A and B viruses. These are viruses that also can cause liver damage and make hepatitis C worse.

• Drinking after hepatitis C cure: Is it safe?
• Liver transplant

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Certain lifestyle changes can help manage hepatitis C. These measures can help keep you healthy longer and protect the health of others:

• Stop drinking alcohol. Alcohol speeds liver disease.
• Don't use medicines that might cause liver damage. Review all medicines you take with your health care provider. You might need to not take certain medicines.

Keep others from coming in contact with your blood. Cover wounds you have. Don't share razors or toothbrushes. Don't donate blood, body organs or semen. Tell health care workers that you have the virus.

Tell your partner about your infection before you have sex. Always use condoms during intercourse.

Preparing for your appointment

If you think you might be at risk of hepatitis C, see your health care provider. If you're diagnosed with a hepatitis C infection, your provider might refer you to a specialist in liver diseases, called a hepatologist, or a specialist in infectious diseases.

What you can do

Consider taking a family member or friend with you to the appointment to help you remember the information you get.

Make a list of:

• Your test results. If you're seeing a liver specialist for the first time after being diagnosed with hepatitis C, write down the results of tests you've had. This includes a liver biopsy to check for damage from chronic infection and a blood test to find which hepatitis C genotype you have.
• Your symptoms, including any that may seem unrelated to the reason for which you scheduled the appointment, and when they began.
• All medicines, vitamins and supplements you take, including doses.
• Questions to ask your health care provider.

Some basic questions to ask about hepatitis C include:

• Should I be tested for other causes of liver disease, such as hepatitis B?
• Has the hepatitis C virus damaged my liver?
• Do I need treatment for a hepatitis C infection?
• What are my treatment choices?
• What are the pros of each treatment option?
• What are the potential risks of each treatment option?
• Is there one treatment you think is best for me?
• I have other medical conditions. How will these affect my hepatitis C treatment?
• Should my family be tested for hepatitis C?
• Is it possible for me to spread the hepatitis C virus to others?
• How can I protect the people around me from hepatitis C?
• Are there brochures or other material that I can have? What websites do you recommend?
• What will decide whether I should plan for a follow-up visit?
• Is it safe for me to drink alcohol?
• What medicines should I avoid?

Be sure to ask all the questions you have about your condition.

What to expect from your doctor

Your health care provider is likely to ask you questions, such as:

• Have you ever gotten donated blood or an organ transplant? If so, when?
• Have you ever given yourself shots of illegal drugs?
• Have you been diagnosed with hepatitis or jaundice?
• Does anyone in your family have hepatitis C?
• Is there a history of liver disease in your family?
• Hepatitis C questions and answers for health professionals. Centers for Disease Control and Prevention. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Accessed March 1, 2023.
• Screening for hepatitis C virus infection in adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Journal of the American Medical Association. 2020; doi:10.1001/jama.2020.1123.
• Chopra S, et al. Overview of the management of chronic hepatitis C virus infection. https://www.uptodate.com/contents/search. Accessed March 1, 2023.
• HCV guidance: Recommendations for testing, managing, and treating hepatitis C. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. https://www.hcvguidelines.org/. Accessed May 1, 2023.
• AskMayoExpert. Hepatitis C (adult). Mayo Clinic; 2021.
• Ferri FF. Hepatitis C. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed March 1, 2023.
• Definition and facts of liver transplant. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/liver-disease/liver-transplant/definition-facts. Accessed March 1, 2023.
• Ami T. Allscripts EPSi. Mayo Clinic. March 24, 2023.
• Hepatitis C: How common is sexual transmission?
• Hepatitis C: What happens in end-stage liver disease?
• New Hep C Treatment
• Why isn't there a hepatitis C vaccine?

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News from mayo clinic.

• Mayo Clinic Minute: What is hepatitis C? March 11, 2024, 03:15 p.m. CDT

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Hepatitis C

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What is hepatitis C?

How common is hepatitis c in the united states, who is more likely to get hepatitis c, should i be screened for hepatitis c, what are the complications of hepatitis c, what are the symptoms of hepatitis c, what causes hepatitis c, how do doctors diagnose hepatitis c, what tests do doctors use to diagnose hepatitis c, how do doctors treat hepatitis c, how do doctors treat the complications of hepatitis c, how can i protect myself from hepatitis c infection, how can i prevent spreading hepatitis c to others, is a hepatitis c vaccine available, what should i eat and drink if i have hepatitis c.

Hepatitis C is a viral infection that causes liver inflammation and damage. Inflammation is swelling that occurs when tissues of the body become injured or infected. Inflammation can damage organs.

Viruses invade normal cells in your body. Many viruses cause infections that can be spread from person to person. The hepatitis C virus spreads through contact with an infected person’s blood.

Hepatitis C can cause an acute or chronic infection.

Although no vaccine for hepatitis C is available, you can take steps to protect yourself from hepatitis C . If you have hepatitis C, talk with your doctor about treatment. Medicines can cure most cases of hepatitis C.

Acute hepatitis C

Acute hepatitis C is a short-term infection. Symptoms can last up to 6 months. Sometimes your body is able to fight off the infection and the virus goes away.

Chronic hepatitis C

Chronic hepatitis C is a long-lasting infection. Chronic hepatitis C occurs when your body isn’t able to fight off the virus. About 75 to 85 percent of people with acute hepatitis C will develop chronic hepatitis C. 13

Early diagnosis and treatment of chronic hepatitis C can prevent liver damage. Without treatment, chronic hepatitis C can cause chronic liver disease, cirrhosis , liver failure , or liver cancer .

In the United States, hepatitis C is the most common chronic viral infection found in blood and spread through contact with blood. 14

Researchers estimate that about 2.7 million to 3.9 million people in the United States have chronic hepatitis C. 13 Many people who have hepatitis C don’t have symptoms and don’t know they have this infection.

Since 2006, the number of new hepatitis C infections has been rising, especially among people younger than age 30 who inject heroin or misuse prescription opioids and inject them. 15,16

New screening efforts and more effective hepatitis C treatments are helping doctors identify and cure more people with the disease. With more screening and treatment, hepatitis C may become less common in the future. Researchers estimate that hepatitis C could be a rare disease in the United States by 2036. 17

People more likely to get hepatitis C are those who

• have injected drugs
• had a blood transfusion or organ transplant before July 1992
• have hemophilia and received clotting factor before 1987
• have been on kidney dialysis
• have been in contact with blood or infected needles at work
• have had tattoos or body piercings
• have worked or lived in a prison
• were born to a mother with hepatitis C
• are infected with HIV
• have had more than one sex partner in the last 6 months or have a history of sexually transmitted disease
• are men who have or had sex with men

In the United States, injecting drugs is the most common way that people get hepatitis C. 13

Doctors usually recommend one-time screening of all adults ages 18 to 79 for hepatitis C. Screening is testing for a disease in people who have no symptoms. Doctors use blood tests to screen for hepatitis C. Many people who have hepatitis C don’t have symptoms and don’t know they have hepatitis C. Screening tests can help doctors diagnose and treat hepatitis C before it causes serious health problems.

Without treatment, hepatitis C may lead to cirrhosis, liver failure, and liver cancer. Early diagnosis and treatment of hepatitis C can prevent these complications.

Cirrhosis is a condition in which the liver slowly breaks down and is unable to function normally. Scar tissue replaces healthy liver tissue and partially blocks the flow of blood through the liver. In the early stages of cirrhosis, the liver continues to function. However, as cirrhosis gets worse, the liver begins to fail.

Liver failure

Also called end-stage liver disease, liver failure progresses over months, years, or even decades. With end-stage liver disease, the liver can no longer perform important functions or replace damaged cells.

Liver cancer

Having chronic hepatitis C increases your chance of developing liver cancer. If chronic hepatitis C causes severe liver damage or cirrhosis before you receive hepatitis C treatment, you will continue to have an increased chance of liver cancer even after treatment. Your doctor may suggest blood tests and an ultrasound or another type of imaging test to check for liver cancer. Finding cancer at an early stage improves the chance of curing the cancer.

Most people infected with hepatitis C have no symptoms. Some people with an acute hepatitis C infection may have symptoms within 1 to 3 months after they are exposed to the virus. These symptoms may include

• dark yellow urine
• feeling tired
• gray- or clay-colored stools
• loss of appetite
• pain in your abdomen
• yellowish eyes and skin, called jaundice

If you have chronic hepatitis C, you most likely will have no symptoms until complications develop, which could be decades after you were infected. For this reason, hepatitis C screening is important, even if you have no symptoms.

The hepatitis C virus causes hepatitis C. The hepatitis C virus spreads through contact with an infected person’s blood. Contact can occur by

• sharing drug needles or other drug materials with an infected person
• getting an accidental stick with a needle that was used on an infected person
• being tattooed or pierced with tools or inks that were not kept sterile—free from all viruses and other microorganisms—and were used on an infected person before they were used on you 
• having contact with the blood or open sores of an infected person
• using an infected person’s razor, toothbrush, or nail clippers
• being born to a mother with hepatitis C
• having unprotected sex with an infected person

You can’t get hepatitis C from

• being coughed or sneezed on by an infected person
• drinking water or eating food
• hugging an infected person
• shaking hands or holding hands with an infected person
• sharing spoons, forks, and other eating utensils
• sitting next to an infected person

A baby can’t get hepatitis C from breast milk. 18

Doctors diagnose hepatitis C based on your medical history, a physical exam, and blood tests. If you have hepatitis C, your doctor may perform additional tests to check your liver.

Medical history

Your doctor will ask about your symptoms and whether you have any history of blood transfusions or injected drug use.

Physical exam

During a physical exam, your doctor will typically examine your body to check for signs of liver damage such as

• changes in skin color
• swelling in your lower legs, feet, or ankles
• tenderness or swelling in your abdomen

Doctors use blood tests to diagnose hepatitis C. Your doctor may order additional tests to check for liver damage, find out how much liver damage you have, or rule out other causes of liver disease.

Blood tests

Your doctor may order one or more blood tests to diagnose hepatitis C. A health care professional will take a blood sample from you and send the sample to a lab.

Blood tests for hepatitis C include the following:

• Screening test for antibodies to the hepatitis C virus. A screening blood test will show whether you have developed antibodies to the hepatitis C virus. A positive antibody test means you were exposed to the hepatitis C virus at some point. However, the virus may no longer be present in your blood if your body fought off the infection on its own or if you received treatment that cured the infection.
• Hepatitis C RNA test. If your antibody test is positive, your doctor will use a hepatitis C RNA test to detect RNA—a type of genetic material—from the hepatitis C virus. The hepatitis C RNA test can show whether you still have the hepatitis C virus and how much virus is in your blood. This information can help your doctor treat the infection. To see if you are responding to treatment, your doctor may order this test while you are undergoing treatment to find out if the amount of virus in your blood is changing.
• Genotype test. Your doctor can use this test to find out what strain, or form, of hepatitis C virus you have. At least six specific strains—called genotypes—of hepatitis C exist. Genotype 1 is the most common hepatitis C genotype in the United States. 1 Your doctor will recommend treatment based on which hepatitis C genotype you have.

Additional tests

If you’ve had chronic hepatitis C for a long time, you could have liver damage. Your doctor may recommend additional tests to find out whether you have liver damage, how much liver damage you have, or to rule out other causes of liver disease. These tests may include

• blood tests
• transient elastography, a special ultrasound of your liver
• liver biopsy , in which a doctor uses a needle to take a small piece of tissue from your liver

Doctors typically use liver biopsy only if other tests don’t provide enough information about a person’s liver damage or disease. Talk with your doctor about which tests are best for you.

Doctors treat hepatitis C with antiviral medicines that attack the virus and can cure the disease in most cases.

Several newer medicines, called direct-acting antiviral medicines, have been approved to treat hepatitis C since 2013. Studies show that these medicines can cure chronic hepatitis C in most people with this disease. These medicines can also cure acute hepatitis C. In some cases, doctors recommend waiting to see if an acute infection becomes chronic before starting treatment.

Your doctor may prescribe one or more of these newer, direct-acting antiviral medicines to treat hepatitis C:

• daclatasvir (Daklinza)
• elbasvir/grazoprevir (Zepatier)
• glecaprevir and pibrentasvir (Mavyret)
• ledipasvir/sofosbuvir (Harvoni)
• ombitasvir/paritaprevir/ritonavir (Technivie)
• ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak, Viekira XR)
• simeprevir (Olysio)
• sofosbuvir (Sovaldi)
• sofosbuvir/velpatasvir (Epclusa)
• sofosbuvir/velpatasvir/voxilaprevir (Vosevi)

Newer medicines are sometimes used along with these older hepatitis C medicines:

• peginterferon alfa-2a (Pegasys) or peginterferon alfa-2b (PEG-Intron)

You may need to take medicines for 8 to 24 weeks to cure hepatitis C. Your doctor will prescribe medicines and recommend a length of treatment based on

• which hepatitis C genotype you have
• how much liver damage you have
• whether you have been treated for hepatitis C in the past

Your doctor may order blood tests during and after your treatment. Blood tests can show whether the treatment is working. Hepatitis C medicines cure the infection in most people who complete treatment.

Hepatitis C medicines may cause side effects. Talk with your doctor about the side effects of treatment. Check with your doctor before taking any other prescription or over-the-counter medicines.

For safety reasons, talk with your doctor before using dietary supplements , such as vitamins, or any complementary or alternative medicines or medical practices.

Cost of hepatitis C medicines

The newer direct-acting antiviral medicines for hepatitis C can be costly. Most government and private health insurance prescription drug plans provide some coverage for these medicines. Talk with your doctor about your health insurance coverage for hepatitis C medicines.

Drug companies, nonprofit organizations, and some states offer programs that can help pay for hepatitis C medicines. If you need help paying for medicines, talk with your doctor. Learn more about financial help for hepatitis C medicines .

If hepatitis C leads to cirrhosis, you should see a doctor who specializes in liver diseases. Doctors can treat the health problems related to cirrhosis with medicines, surgery, and other medical procedures. If you have cirrhosis, you have an increased chance of liver cancer. Your doctor may order an ultrasound test to check for liver cancer.

If hepatitis C leads to liver failure or liver cancer, you may need a liver transplant .

If you don’t have hepatitis C, you can help protect yourself from hepatitis C infection by

• not sharing drug needles or other drug materials
• wearing gloves if you have to touch another person’s blood or open sores
• making sure your tattoo artist or body piercer uses sterile tools and unopened ink
• not sharing personal items such toothbrushes, razors, or nail clippers

Hepatitis C can spread from person to person during sex, but the chances are low. People who have multiple sex partners, have HIV or other sexually transmitted diseases, or who engage in rough or anal sex have a higher chance of getting hepatitis C. Talk with your doctor about your risk of getting hepatitis C through sex and about safe sex practices , such as using a latex or polyurethane condom to help prevent the spread of hepatitis C. 

If you had hepatitis C in the past and your body fought off the infection or medicines cured the infection, you can get hepatitis C again. Follow the steps above, and talk with your doctor about how to protect yourself from another hepatitis C infection. 

If you think you may have been exposed to the hepatitis C virus, see your doctor as soon as possible. Early diagnosis and treatment can help prevent liver damage.

If you have hepatitis C, follow the steps above to avoid spreading the infection. Tell your sex partner you have hepatitis C, and talk with your doctor about safe sex practices. In addition, you can protect others from infection by telling your doctor, dentist, and other health care providers that you have hepatitis C. Don’t donate blood or blood products, semen, organs, or tissue.

Researchers are still working on a vaccine for hepatitis C. If you have hepatitis C, talk with your doctor about vaccines for hepatitis A and hepatitis B . These vaccines can protect you from hepatitis A and hepatitis B infections, which could further damage your liver.

If you have hepatitis C, you should eat a balanced, healthy diet. Talk with your doctor about healthy eating. You should also avoid alcohol because it can cause more liver damage.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

The NIDDK would like to thank: Adrian M. Di Bisceglie, M.D., Saint Louis University School of Medicine

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Lesson 5. Diagnosis of Acute HCV Infection

Learning objective performance indicators.

• Define acute HCV infection
• Recognize the clinical features, if present, in persons with acute HCV infection
• Describe the timing of positivity with HCV RNA and HCV antibody tests after acquisition of HCV
• List appropriate laboratory tests required to make a diagnosis of acute HCV infection
• Summarize the approach for laboratory testing following a known exposure to HCV

Definitions of Acute HCV Infection

Terminology related to acute hcv infection, clinical manifestations, relationship of symptoms and spontaneous clearance, clinical scenarios that suggest acute hcv infection, hcv rna (hcv nucleic acid testing), antibodies to hcv, hepatitis c core antigen, alanine aminotransferase (alt), establishing a diagnosis of acute hcv, potential missed diagnosis of acute hcv infection, laboratory testing following known exposure to hcv, cdc case definition for acute hepatitis c, summary points, additional references, definition of acute hcv.

Acute hepatitis C virus (HCV) infection is defined as the 6-month period following the acquisition of hepatitis C virus. [ 1 , 2 , 3 ] This definition does not take into account whether the patient has clinical signs or symptoms of acute hepatitis. [ 2 ] The rationale for choosing 6 months as the time period to define acute infection is based on evidence that most individuals who spontaneously clear HCV will do so by 6 months. [ 4 , 5 , 6 ]

Various terms have been used to refer to acute hepatitis C infection, including acute infection, acute phase infection, very early infection, recent infection, and newly acquired infection. Very early infection typically refers to patients with a positive HCV RNA and documented HCV antibody seroconversion, with this scenario being the most definitive for diagnosing acute HCV infection. Some experts have suggested limiting the terminology for acute HCV infection to acute infection and recent infection: [ 2 ]

• Acute Infection : estimated duration of infection less than 6 months
• Recent Infection : estimated duration of infection longer than 6 months, but shorter than 2 years.

Clinical Features of Acute HCV

Among individuals with acute HCV infection, only 15 to 25% develop a clearly distinguishable symptomatic illness. [ 7 , 8 , 9 ] In addition, most chronically infected patients cannot recall a time when they were acutely symptomatic. When patients develop symptomatic acute HCV infection, the clinical manifestations typically resemble those that occur with other types of viral hepatitis—fatigue, myalgias, low-grade fever, jaundice, dark urine, nausea, vomiting, right upper quadrant pain. [ 8 , 10 ] Symptoms may consist of malaise only, without jaundice or gastrointestinal symptoms ( Source: Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125:80-8. " class="linked-doc-1 style-text-width-below document has-link-relation link-relation-below" href="//cdn.hepatitisc.uw.edu/doc/14-4/symptoms-acute-hcv-infection.jpg">Figure 1 ). If symptoms from acute infection develop, they usually do so within 4 to 12 weeks (mean 7 to 8 weeks) after infection has occurred, and they typically persist for 2 to 12 weeks. [ 7 , 8 , 11 ] Fulminant hepatic failure due to acute HCV infection very rarely occurs, but preexisting chronic hepatitis B infection or steatotic liver disease can increase this risk. [ 12 , 13 , 14 ]

Overall, the estimated rate of spontaneous clearance of HCV infection varies widely in the literature from 15 to 60%. [ 15 , 16 , 17 , 18 ] The rates of spontaneous clearance are significantly lower (in the range of only 10 to 20%) in Black person and in those individuals who have HIV coinfection. [ 19 , 20 ] In contrast, rates of spontaneous clearance are higher in females and in persons who acquired HCV in childhood. [ 21 , 22 ] It has also been demonstrated that patients who present with symptomatic acute HCV infection and jaundice have higher rates of spontaneous clearance of HCV, in the range of 35 to 50%. [ 8 , 16 , 23 ] The presence of jaundice is believed to reflect hepatic inflammation caused by a more robust initial immune response against HCV. [ 6 , 16 ]

Symptomatic Presentation

Individuals with acute HCV infection can develop significant symptoms and may present with the new onset of jaundice, fatigue, nausea, abdominal pain, and malaise. More often, however, these individuals have no obvious symptoms or have limited symptoms, such as slight malaise.

History of a Recent HCV Exposure but Without Symptoms

Since acute HCV is usually asymptomatic, clinicians should test a person for HCV if there is a history of potential HCV exposure, regardless of clinical symptoms. The most common exposures include recent injection drug use that involved sharing needles or other injection works, a needlestick injury, and sexual contact with a partner who has known HCV infection. For persons with acute or recent HCV acquisition, HCV testing soon after the exposure can make the diagnosis of a new infection and distinguish acute from chronic infection. Recent injection drug use with shared needles or equipment would be considered the highest risk exposure, especially if the needle-sharing partner is known to have HCV. Although the exact risk of acquiring HCV through sexual contact is controversial, sexual transmission appears to be highest among men who have sex with men (MSM), particularly among MSM with HIV and MSM who have engaged in physically traumatic or rough sex. [ 24 ]

Laboratory Studies Used for the Evaluation of Initial HCV Infection

The key laboratory studies utilized in the evaluation of possible acute hepatitis C are HCV RNA, anti-HCV, and alanine aminotransferase (ALT). Patients who become infected with HCV will typically develop abnormal laboratory findings in the following order: detectable HCV RNA, followed by elevation in ALT, and then anti-HCV ( Source: Centers for Disease Control and Prevention (CDC). " class="linked-doc-2 style-text-width-below document has-link-relation link-relation-below" href="//cdn.hepatitisc.uw.edu/doc/16-3/laboratory-markers-acute-hcv-infection.jpg">Figure 2 ). [ 8 , 25 ] Patients who develop a clinical illness with acute HCV infection usually have onset of symptoms well after the onset of viremia, but soon after, or concomitant with, increases in ALT levels.

In most patients, HCV RNA can be detected in blood within 1 to 2 weeks after infection. [ 26 ] The HCV RNA test is often referred to as an HCV nucleic acid test (NAT) or nucleic acid amplification test (NAAT). This period from infection until HCV RNA is detectable in plasma by a commercially available assay is referred to as the previremic (or eclipse) phase. [ 26 , 27 ] During the eclipse phase, HCV has likely established infection in susceptible hepatocytes, and, in some patients, the use of qualitative HCV RNA assays with very high sensitivity will reveal HCV RNA in blood. [ 26 ] The eclipse phase is followed by an 8- to 10-day “ramp-up” phase in which HCV replication increases exponentially and readily becomes detectable in plasma; the HCV RNA levels typically peak 6 to 10 weeks after infection (“plateau phase”) and remain near these peak levels for about 40 to 60 days ( Source: Glynn SA, Wright DJ, Kleinman SH, et al. Dynamics of viremia in early hepatitis C virus infection. Transfusion. 2005;45:994-1002. Illustration: David H. Spach, MD " class="linked-doc-3 style-text-width-below document has-link-relation link-relation-below" href="//cdn.hepatitisc.uw.edu/doc/18-3/acute-hcv-infection-viral-dynamics.jpg">Figure 3 ). [ 26 ] Detection of HCV RNA during acute infection is not entirely reliable as HCV RNA levels may fluctuate significantly during this period—in some instances, HCV RNA levels fall below detectable levels. [ 7 , 26 , 28 ] At the onset of symptoms, however, detectable HCV RNA levels are uniformly present.

Antibodies to HCV typically become detectable about 50 to 60 days after infection (range 20 to 150 days); the detection of HCV-specific antibodies significantly lags behind detectable HCV RNA levels. [ 7 , 8 , 26 ] After 12 weeks, more than 90% of patients will have a positive HCV antibody test. The period from initial infection until seroconversion is often referred to as the “serologic window period” ( Illustration: David H. Spach, MD " class="linked-doc-4 style-text-width-below document has-link-relation link-relation-below" href="//cdn.hepatitisc.uw.edu/doc/19-2/acute-hcv-infection-serologic-window-period.jpg">Figure 4 ). [ 29 , 30 ] The use of an HCV antibody test as the sole means to diagnose acute HCV is not reliable, since only approximately 50 to 70% of patients have detectable HCV antibodies at the onset of symptoms. In addition, a positive HCV antibody test, which measures both IgM and IgG, does not differentiate acute from chronic HCV infection. Further, IgM antibody is not a reliable indicator of recent infection since it can persist for months in persons with chronic hepatitis C infection.

The HCV capsid proteins, which are also referred to as HCV core, make up a spherical capsid (core) structure that surrounds and protects HCV RNA ( Illustration: Cognition Studio, Inc. " class="linked-doc-5 style-text-width-below document has-link-relation link-relation-below" href="//cdn.hepatitisc.uw.edu/doc/511-3/hepatitis-c-capsid.jpg">Figure 5 ). [ 31 , 32 ] Several studies have shown testing for HCV core antigen can enhance the diagnostic yield of persons with acute HCV when compared with HCV antibody testing alone. [ 30 , 33 , 34 ] The HCV antigen assays that have been developed for diagnostic purposes include HCV core antigen assays and a combination HCV antibody-HCV core antigen assay. [ 35 , 36 , 37 ] Although some experts have proposed using HCV core antigen testing as a less expensive option than HCV RNA testing for detecting acute HCV with similar sensitivity, there are no HCV antigen assays (or HCV antigen-antibody combination assays) that are FDA-approved for use in the United States. [ 38 , 39 ]

Within 4 to 12 weeks after HCV infection, most patients will have some degree of liver cell injury, as manifested by an elevation in serum ALT levels. Typically, the increases in ALT follow the presence of detectable HCV RNA levels by about 1 to 2 weeks but generally precede the development of HCV antibodies. The mean ALT level after acute infection can reach the 800 IU/L range. The Centers for Disease Control and Prevention uses an increase in ALT to a peak level greater than 200 IU/L during the period of acute illness as part of the diagnostic criteria.

In the United States, the gold standard for the laboratory diagnosis of acute HCV is an HCV antibody seroconversion (documented negative HCV antibody test followed by a positive antibody test), combined with a positive HCV RNA test and elevated ALT. In clinical practice, many patients do not present with these paired antibody results and often, not in a timely fashion to diagnose acute infection. Thus, a probable diagnosis of acute HCV is made when an individual has a positive HCV RNA and evidence of a negative HCV antibody in the prior 6 months. It can be challenging to differentiate acute infection from chronic infection in patients who have not previously undergone HCV antibody testing.

In many laboratories in the United States, HCV testing protocols are in place whereby a positive HCV antibody test triggers automatic (reflex) testing of the sample for HCV RNA, whereas a negative initial HCV antibody test does not trigger further testing. This reflex protocol is ideal for detecting persons with chronic HCV infection and determining whether these individuals have resolved or chronic (active) infection. This protocol, however, can be problematic in the setting of acute HCV since HCV antibody seroconversion may not yet have taken place, and the HCV RNA test will not be run, thereby resulting in a false-negative HCV test. If a patient has suspected acute HCV infections, clinicians should inquire whether the laboratory performing the HCV testing uses a reflex testing protocol; if an HCV reflex testing protocol is in place, the clinician should intentionally place separate orders for the HCV antibody and the HCV RNA so that both tests will be run, regardless of the HCV antibody result. This approach, in the setting of suspected acute HCV infection, will allow for detection of HCV if the individual has not been infected with HCV long enough to have generated HCV antibodies.

In situations where patients have encountered high-risk exposures, serial laboratory testing is the key to promptly establishing the diagnosis of acute HCV infection. The following briefly outlines the recommended sequence of laboratory testing following a known exposure to hepatitis C virus ( " class="linked-doc-6 style-text-width-below document has-link-relation link-relation-bottom" href="//cdn.hepatitisc.uw.edu/doc/464-4/laboratory-evaluation-persons-exposed-to-hcv.jpg">Figure 6 ):

• At Initial Presentation : HCV antibody, HCV RNA, and ALT
• At 4 Weeks from Time of Suspected Exposure : HCV RNA and ALT
• At 12 Weeks from Time of Suspected Exposure : HCV antibody, HCV RNA, and ALT
• At 24 Weeks from Time of Suspected Exposure : HCV antibody and HCV RNA

The Centers for Disease Control and Prevention (CDC) has established criteria for the 2020 case definition of acute Hepatitis C. [ 40 ] This definition utilizes clinical criteria, laboratory criteria for diagnosis, criteria to distinguish a new case from an existing case, and a case classification (probable or confirmed). [ 40 ]

• Acute HCV infection is usually defined as an estimated duration of infection of less than 6 months.
• Most patients with acute HCV infection do not have a symptomatic illness or have very mild nonspecific symptoms that may include malaise, anorexia, and abdominal pain.
• In the less common situation when patients do develop symptomatic acute HCV infection, they most often present with jaundice, dark urine, nausea, abdominal pain, and malaise.
• The key laboratory studies utilized in the evaluation of possible acute hepatitis C are HCV RNA, HCV antibody, and ALT; the HCV antibody and the HCV RNA tests should be ordered simultaneously and as separate orders, not as an HCV antibody/HCV RNA reflex test, which can miss acute HCV infection.
• With acute HCV, patients usually first have detectable HCV RNA, followed by elevation in ALT, and then followed by development of HCV antibody.
• The gold standard for diagnosis is HCV antibody seroconversion combined with a positive HCV RNA test and elevated ALT.
• Acute HCV infection can rarely cause a life-threatening illness.
• The CDC 2020 case definition for acute hepatitis C includes clinical criteria, laboratory criteria, case classification as probable or confirmed, and criteria to distinguish a new case from an existing case.
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INTRODUCTION

This topic addresses the general management of patients with chronic HCV infection. Patient selection for treatment and specific treatment regimens are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults" and "Direct-acting antivirals for the treatment of hepatitis C virus infection" .)

Other guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL) [ 2 ]. World Health Organization (WHO) also released guidelines in 2014 on screening and treatment of HCV, intended primarily for clinicians and policy-makers in low- and middle-income countries [ 3 ].

Links to these and other guidelines can be found below. (See 'Society guideline links' below.)

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• v.19(44); 2013 Nov 28

An insight into the diagnosis and pathogenesis of hepatitis C virus infection

Correspondence to: Mohammad Irshad, Professor, Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India. moc.oohay@45dahsrird

Telephone: +91-11-26594981 Fax: +91-11-26588663

This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus (HCV) infection over the last few decades. The information based on published literature provides an update on these two aspects of HCV. HCV infection, previously called blood transmitted non-A, non-B infection, is prevalent globally and poses a serious public health problem worldwide. The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction (PCR) technique. Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles. Moreover, multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes. In contrast to previous methods, the newly developed assays are not only fast and economic, but also resolve the problem of the window period as well as differentiate present from past infection. HCV is a non-cytopathic virus, thus, its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress, insulin resistance and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV-quasispecies and several metabolic factors regulating liver metabolism. HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.

Core tip: This article focuses on the diagnosis and pathogenesis of hepatitis C virus infection. Both of these aspects are important in order to eradicate this endemic virus and to prevent serious liver diseases.

INTRODUCTION

Hepatitis C virus (HCV) was first characterized by Choo et al[ 1 ] and Kuo et al[ 2 ] in 1989. It was soon identified as the main causative agent of the disease previously known as post transfusion non-A, non-B hepatitis virus infection. HCV has been found to be an important cause of liver disease and remains a major public health problem worldwide. According to the World Health Organization, nearly 3% of the world population has been infected with HCV. Therefore, more than 170 million people are chronic carriers of HCV and at high risk of developing liver cirrhosis and/or hepatocellular carcinoma (HCC). Three to 4% of chronically infected individuals develop fatal HCC. Currently, HCC caused by HCV infection is considered an indication for liver transplantation[ 3 - 5 ].

HCV was the leading cause of post-transfusion and community-acquired non-A, non-B hepatitis until characterization of the virus in 1989 and the introduction of blood screening in 1990. The initiation of blood screening for HCV has markedly reduced its incidence. However, it still remains a significant problem in intravenous drug abusers. HCV infection is the most common cause of liver transplantation in adults. HCV and HIV-1 frequently co-infect humans and it has been estimated that as many as 18% of HIV-infected persons are also infected with HCV[ 4 ].

HCV is an enveloped RNA virus and belongs to the genus Hepacivirus of the family Flaviviridae. The HCV genome consists of 9.6-kb single-stranded RNA of positive polarity and a single open reading frame of 9033-9099 nucleotides flanked by a conserved 5’ and 3’ noncoding region (NCR) at the ends. Its genome codes for a long polyprotein of approximately 3000 amino acids[ 6 ] which is processed co-translationally and post-translationally to yield structural proteins (core, envelope E1, and E2) and non-structural (NS) proteins (NS1/p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B)[ 7 ]. The envelope proteins (E1 and E2) are the outer surface proteins of the viral particles and play important roles in virus entry into the host cell. NS5B is a variable region of the HCV genome and codes for an RNA-dependent RNA polymerase (RdRp).

RNA polymerase lacks proof reading activity and this may alter the detection, sensitivity to interferon anti-viral activity and pathogenicity of the virus (Figure ​ (Figure1 1 )[ 8 ].

Proteins encoded by the hepatitis C virus genome. Genome organization of hepatitis C virus showing the structure of the viral genome, including the long open reading frame encoding structural and nonstructural proteins, and 5’ and 3’ non-coding regions (NCRs). [Source: Monica A et al. Expert Rev Mol Med 2003; 5].

Like several other viruses, the RNA virus has a high degree of heterogeneity[ 5 ] that varies 30%-35% among different genotypes. Based on previous studies, six major genotypes and more than 120 subtypes of HCV have been characterized to date[ 9 ]. These HCV genotypes have distinct geographic distributions, with genotype 1 and 2 frequently found worldwide[ 10 ]. In India, genotype 3 is reported to be the most prevalent, followed by genotype 1[ 11 , 12 ]. Different HCV genotypes have important epidemiological implications. Despite nucleotide sequence divergence between genotypes, they remain quite similar in their transmission pattern, persistence and disease development[ 13 ]. Although genetic variation is attributed to several factors, two major theories i.e ., the Darwinian and Neutral evolution theories are thought to be the prominent theories in causing genetic diversity in HCV[ 13 ]. The nucleotide sequence variability is distributed throughout the viral genome. Regions encoding envelope proteins (E1, E2) and NS-1 are the most variable, whereas the 5’ NCR is the most conserved region.

HCV patients show a poor response to antiviral therapy based on the combination of pegylated interferon (IFN)-α and ribavirin. Only 40%-50% of patients infected with HCV genotype-1 and 80% of those infected with genotype-2 or 3 achieve a sustained virological response (SVR) with this regimen[ 14 ]. The recent use of direct acting anti-viral (DAA) molecules, which are active on HCV during treatment, has led to a substantial improvement in SVR rates in HCV genotype-1 infected patients. However, this may lead to the selection of resistant virus if DAA molecules are used alone[ 15 ]. Moreover, there is a high relapse rate of HCV infection after discontinuation of therapy. Recently, host genetic factors including human leukocyte antigen (HLA) and cytokine genes have been implicated in HCV infection or persistence[ 16 ]. Genetic polymorphism of cytokine genes including IFN- γ, tumor necrosis factor ( TNF ) - α, interleukin ( IL ) -10 , IL-20 and SNPs in the promoter region of osteopontin gene, have been found to be crucial in determining the therapeutic outcome of HCV infection[ 17 ]. Therefore, every effort is being made to understand the pathogenesis of HCV infection to create a therapeutic model for an effective treatment against HCV. Although recent reports describe the development of in vitro replication systems leading to the production of infectious viral particles[ 18 , 19 ], there is currently no cell culture model suitable for synthesizing vaccines based on killed or attenuated virus. All efforts have been focused on sub-unit vaccines, composed of one or several antigens, either in the form of recombinant proteins, synthetic peptides or vectored vaccines. The earliest vaccine developed for HCV was that by the Chiron group[ 20 ]. However, very little progress was noted in this direction in subsequent years.

This article reviews the major aspects of HCV infection including the diagnosis and pathogenesis of HCV infection. Both of these aspects have a strong association with therapy, thus, newer means of accurate diagnosis and a better understanding of HCV infection pathogenesis may allow the development of a therapeutic model. This article attempts to update readers regarding the information available on these two aspects to date.

DIAGNOSIS OF HCV INFECTION

During HCV infection, every attempt is made to diagnose and differentiate acute from chronic hepatitis C infection. Acute HCV infection is typically mild. It is often not diagnosed, and the infection may be recognized only when it becomes chronic[ 21 ]. The diagnostic tests used, including the presence of anti-HCV antibodies in serum, cannot differentiate between acute and chronic HCV infection because anti-HCV IgM, used as marker of acute infection, is variable in acute infectious disease and is also detected at high rates in patients with chronic HCV infection[ 22 , 23 ]. The diagnostic procedures for hepatitis C virus infection used in laboratories are based on the detection of anti-HCV antibodies against recombinant HCV proteins using enzyme immunoassay (EIA) and chemiluminescence immunoassay. Non-structural and recombinant antigens are used in these assays. Four different generations of anti-HCV test kits have been developed to date. The first generation EIA detected antibodies against the nonstructural proteins (NS4) with recombinant antigen c100-3. Subsequently, the second generation assay was developed and this included antigens from the core region (c22-3), the NS3 region (c33c) and a part of c100-3 (5-1-1) from the NS4 region. The third-generation EIA included an additional antigen from the NS5 region and a reconfiguration of the core and NS3 antigens. However, all these anti-HCV assays had the disadvantages of giving high false positive results and a lack of sensitivity to detect antibodies during the window period. In addition, these antibody-based assays could not distinguish between acute, past and chronic infections. This was followed by the development of supplementary tests involving the recombinant immunoblot assay (RIBA) which was commercialized. This assay contained recombinant antigen (c33c, NS5) and synthetic peptides (5-1-1, c100 and c22). Similarly, a few other commercial assays, known as third generation immunoassays incorporated HCV antigens from the core region, E2 hypervariable region, NS3 region, NS4A, NS4B and NS5A region. All these recombinant immunoblot assays were used as supplementary tests to the anti-HCV assays. Similar to EIA, the RIBA had the disadvantages of difficulty in performance and a high percentage of indeterminate results. Therefore, these are no longer used in diagnostic laboratories. Recently, fourth generation anti-HCV assays incorporating additional nonstructural proteins are being used as screening tests[ 24 ]. These kits for anti-HCV detection target different HCV antigens and detect more than five primary antibodies to ensure the specificity and sensitivity of the detection kit.

Anti-C22c and anti-C33c may be the first HCV antibodies to appear during the acute phase of the disease, which is defined by elevated alanine aminotransferase (ALT) levels and/or clinical symptoms[ 25 ]. Anti-NS5 appears somewhat later, while anti-C100-3 is the last antibody to be detected in acute self-limited HCV infection. The diagnosis and differentiation of acute from chronic HCV infection poses another problem. Patients chronically infected with one HCV-genotype develop acute hepatitis on infection with another genotype. Multiple episodes of acute hepatitis were observed in polytransfused thalassemic children reinfected with different HCV genotypes[ 26 , 27 ]. Therefore, discrimination between acute and chronic infection in the same patient is sometimes very difficult. HCV RNA in the serum or liver appears to be the earliest detectable marker of acute HCV infection, preceding the appearance of anti-HCV by several weeks[ 25 ]. HCV viremia may persist despite the normalization of serum ALT levels. Thus, the use of ALT levels in the diagnosis of HCV is not helpful. However, HCV RNA in serum usually lasts for fewer than 4 mo in patients with acute self-limited HCV infection. The average time from transfusion to sero-conversion is approximately 11 to 12 wk with EIA-1 (Enzyme immunoassay-1) and 7 to 8 wk with EIA-2 (Enzyme immunoassay-2). Now attempts are being made to develop EIA assays to differentiate HCV sub-types[ 28 ]. Patients with post-transfusion chronic non-A, non-B hepatitis develop anti-HCV antibodies in the majority of cases. Anti-HCV antibodies are not neutralizing, especially with HCV envelope proteins E1 and E2[ 29 ]. High levels of anti-C100-3 were correlated with high titers of circulating HCV in chimpanzees[ 30 ]. Therefore, the development and persistence of diagnostic antibodies to HCV seem to reflect concomitant virus replication and consequently a high potential for infectivity.

HCV RNA is frequently detected in patients with chronic hepatitis C and in patients carrying anti-HCV antibodies. A study carried out in Hong Kong demonstrated that 83% of anti-HCV positive patients were viremic when HCV RNA was determined using polymerase chain reaction (PCR) with two different sets of primers for noncoding regions[ 27 ]. Similarly, in another study, 98 of 100 patients with chronic non-A, non-B liver disease were positive for antibodies by EIA-2, but all 100 patients were positive for HCV RNA by PCR. With the currently available EIA systems, chronic HCV infection can readily be identified in most patients. Measurement of HCV RNA by PCR does not substantially increase the numbers of patients found to have chronic HCV infection[ 31 ]. Following the introduction and wider use of real-time PCR, it is now easier to diagnose and monitor the progress of HCV viremia in a very short time period[ 32 ]. In addition, the use of multiplex PCR by real time is another advancement in the detection of possible hepatitis viral co-infections in single attempt analysis[ 33 ].

Based on published information regarding various aspects of HCV infection including the currently available diagnostic assays and therapeutic regimens, the American Association for the Study of Liver Diseases and Centers for Disease Control and Prevention, United States have approved a document as “practice guidelines” for use in the diagnosis and treatment of HCV infection. This is an important document and describes details of the guidelines to be followed for laboratory diagnosis of acute/chronic HCV infection[ 34 ].

PATHOGENESIS OF HCV INFECTION

HCV is a non-cytopathic virus[ 35 ] that enters the liver cell and undergoes replication simultaneously causing cell necrosis by several mechanisms including immune-mediated cytolysis in addition to various other phenomena such as hepatic steatosis, oxidative stress and insulin resistance. The proteins/peptides encoded by different sub-genomic regions of the HCV genome and their quasispecies influence the above mechanism, and thus, have a significant role in HCV pathogenesis and disease causation. A brief description of HCV pathogenesis in the light of these factors is given in the following section (Figure ​ (Figure2 2 ).

Regulation of hepatitis C virus pathogenesis by host immunity and metabolic factors. HCV: Hepatitis C virus.

Viral entry

HCV is a blood-transmitted virus that reaches the liver via circulation. The entry of HCV isolates requires at least 4 host-derived factors including scavenger receptor class B type I, Occludin, Claudin-I (CLDNI) and CD81. In addition, CLDN6 and CLDN9 have been shown to substitute for CLDN1 as HCV entry factors in human non-liver cells[ 36 ]. The CD81 molecule on host cell surfaces acts as a viral receptor, which binds with the viral particle and facilitates its entry in the liver cell[ 37 , 38 ]. CD81 is expressed on the surface of almost all nucleated cells and complexes with a variety of other cell-surface receptors such as CD19 and CD21 on B cells, and sends a costimulatory signal to the cells[ 39 ]. The viral envelop protein, E2, binds to the major extracellular loop of CD8[ 40 ]. HCV shows multi-site binding and can also bind to several other molecules such as the receptor for low-density lipoprotein, the dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), and its liver counterpart[ 41 , 42 ]. E2 is the most variable viral protein, and therefore, its interactions with CD81 have been reported to be strain-specific[ 43 ]. It has two hyper variable regions, HVR-1 and HVR-2 which undergo frequent mutations, possibly due to virus-neutralizing antibodies and HCV-specific cytolytic T lymphocytes (CTLs). HCV also has a high mutation rate due to the lack of proofreading ability of its RNA-dependent RNA polymerase. Therefore, HCV exists in several distinct, but closely related virus species within an infected individual. These species are called HCV quasispecies.

HOST IMMUNITY

Innate immunity.

Innate immunity presents a first line defense for the control of HCV infection as it does for several other viral infections. During HCV infection, cells produce Type 1 IFN which prepares and induces the cells to resist infection, check viral replication, promote adaptive immunity and activate natural killer (NK) cells, DCs and Kupffer cells etc . Once inside the cell, the innate immunity vs HCV is triggered through host recognition of viral macromolecular motifs, known as pathogen-associated molecular patterns (PAMPs), as non-self by cellular pathogen recognition receptors. These receptors includes toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I) like receptors (RLRs)[ 44 ]. RIG-I binds PAMP on HCV-RNA and activates interferon regulatory factor-3 (IRF-3) for expression of IFN-α/β and anti-viral/interferon stimulated genes (ISGs)[ 45 ]. The secreted IFN and cytokines then activate NKs, DCs and Kupffer cells etc . These cells also play a significant role in mounting T/B cell-based immunity[ 46 ]. The PAMP region lies on the 3’ untranslated region (UTR) of HCV and induces RIG-1 signaling[ 47 ] that results in a RIG-1 interaction with IFN-β promoter stimulator (IPS-1) which causes activation of IRF-3 and nuclear factor κB (NFκB).

HCV can effectively evade innate immunity resulting in persistent viral infection. This occurs because HCV has evolved to counteract the RIG-1 pathway[ 48 ] and thus evade the immune challenge. This phenomenon is the reason for chronicity in the majority of HCV infected patients. For this, the non-structural proteins of HCV i.e ., NS3 and NS4A form a complex which activates the NS protease domain to target cleavage of IPS-1. After cleavage, IPS-1 can no longer signal downstream to activate IRF-3 and NFκB and the infected cells no longer produce IFN-β or express ISGs[ 49 ].

NK cells, a major arm of innate immunity, play an important role in eradication of HCV. The liver is enriched in NK cells that are usually activated in an early phase of HCV infection. The activated NK cells recruit virus-specific T cells and induce antiviral immunity in the liver. They also eliminate virus-infected hepatocytes directly by cytolytic mechanisms and indirectly by secreting cytokines including IFN-γ and TNF-α. These cytokines induce an antiviral state in host cells. Surprisingly, HCV has evolved multiple strategies to counter the host’s NK cell response. It is interesting that activated NK cells contribute toward liver injury, while inactive or compromised NK cells permit the virus to continue invasion[ 50 ].

Adaptive immunity

After entry and replication of the virus inside liver cells, the viral molecules are transported to the endoplasmic reticulum and associate with major histocompatibility complex (MHC) molecules, which are finally transported to the cell surface. These molecules on the cell surface are recognized by T cells for their immune action. The majority of CTLs are CD8 + and recognize antigens presented on MHC class I molecules. Approximately 10% of CTLs are CD4 + which recognize antigens presented on MHC II molecules. These CTLs eliminate cells infected with virus. However, HCV is reported to have evolved mechanisms to avoid recognition by CTLs. They either reduce the expression of MHC molecules or prevent the viral peptide from presentation at the cell surface. Thus, CTLs play a major role in viral eradication[ 51 ] and immunopathogenesis of HCV infection[ 52 ].

In another pathway of the disease mechanism, the destruction of HCV-infected hepatocytes release HCV fragments that are taken up by myeloid DCs. These DCs migrate to the draining lymph nodes and express HCV antigens on HLA class II molecules. Subsequently, they increase expression of costimulatory molecules (CD80, CD86) which interact with and activate antigen-specific helper T (Th) cells[ 53 ]. These activated Th cells promote the maturation of DCs and increase the expression of CD40 ligand and TNF-α. The mature DCs induce T-cell activation by overexpression of their surface molecules. They also enhance antigen presentation capacity via HLA-I and production of cytokines that stimulate T-cell activation. IL-12 has been shown to play an important role in stimulating IFN-γ production from activated T cells[ 54 , 55 ], and thus, induces development of the type 1 (Th1) immune response characteristic of CTL activation. The effector CTLs release perforin, granzyme, and TNF-α, or express Fas ligand, and initiate a direct attack on HCV-infected hepatocytes[ 56 , 57 ].

The hepatocytes infected with HCV and DCs produce Type I IFNs which suppress viral replication by inducing enzymes such as 2’-5’ oligoadenylate synthetase (OAS) and RNA-dependent protein kinase (PKR) in hepatocytes[ 58 ]. The plasmacytoid DC recognizes HCV-related markers through TLR-7, which interacts with single-stranded RNA[ 59 ]. The TLR-signaling up-regulates PDC-triggering receptor expressed on myeloid cells (PDC-TREM) which induce further production of IFN-α[ 60 ]. Activated OAS destroys viral RNAs, whereas PKR inhibits forming polysomes of viral mRNA[ 58 ]. When HCV-specific CTL responses are not strong enough to eradicate the virus this leads to persistent infection[ 61 ].

Successful clearance of HCV during acute HCV infection depends on the rise, vigor and persistence of the Th1 immune response[ 62 , 63 ]. Patients who developed a strong Th1 response showed efficient viral clearance and a self-limited disease course. In contrast, those who lacked IL-12 and IFN-γ production invariably developed chronic persistence of the virus. The majority of patients fail to control the infection and develop a chronic infection with a variable degree of hepatitis and viremia[ 64 , 65 ]. Experimental studies have also demonstrated that HCV components induce an antigen processing mechanism and IFN-stimulated genes in infected livers[ 66 - 68 ]. Impaired function of DCs, as antigen-presenting cells in inducing immunity, may be responsible for the impaired immune responses. Various studies have reported that viral proteins including HCV core, E1, and NS3 inhibit DC maturation[ 69 , 70 ]. HCV infects DCs through the binding of HCV E2 protein and thereby suppress DC function in promoting an antiviral effect[ 41 , 71 ].

CTLs activated by viral proteins, not only kill virus-infected cells, but also contribute to virus control through a noncytolytic mechanism by secreting cytokines, e.g ., IFN-γ, IFN-α/β and TNF-α. These cytokines induce an antiviral state in host cells. This also renders uninfected cells resistant to infection and prevents viral replication. The progression of the majority of infected persons to chronic infection suggests inability of the antiviral immunity to contain this infection. There may be several reasons for this failure, including the emergence of escape variants as a result of a high rate of virus mutations, decreased production of antiviral cytokines or “stunning” of HCV-specific CTLs, a compromised cytolytic potential of the CTLs and antagonistic peptides[ 72 ].

It is important to note here that the HCV genome in a single host is a dynamic population of different, but closely related genomes, designated quasispecies. The generation of quasispecies is usually ascribed to high variation in hyper variable region-1 (HVR-1) during viral replication[ 73 ]. In acute resolving hepatitis, HVR-1 shows very little variation, as compared to that in chronic hepatitis[ 74 ]. HVR-1 induces anti-HCV neutralizing antibodies[ 75 , 76 ] and HVR-1 specific CD4 + and CD8 + T cells[ 77 , 78 ]. Using the responding host cellular immune response differentially, HVR-1 favors viral escape[ 79 , 80 ]. HVR-1 variations result from the action of a continuous immune-driven positive selection[ 81 , 82 ]. Thus, HVR-1 complexity helps in the virus adaptive strategy to escape the immune onset. HCV clearance is associated with a vigorous HCV specific CD4 + and CD8 + T cell response in the acute phase of infection. In contrast, viral persistence is associated with a weak and dysfunctional virus specific T cell response[ 79 - 83 ]. T cell failure and HCV immune evasion have been explained in several reports[ 84 - 86 ].

Role of T regulatory cells in adaptive immunity

Recent studies have suggested a possible role for different regulatory T cell populations in HCV persistence. These studies showed a higher frequency of CD4 + CD25 + regulatory T cells in the blood and CD4 + FoxP3 + T cells in the liver of chronically HCV infected patients[ 87 - 89 ]. CD4 + CD25 + regulatory T cells suppress HCV specific CD8 + T cell and CD4 + T cell proliferation as well as CD8 + T cell IFN-γ secretion[ 87 , 90 - 92 ]. After HCV antigen stimulation, Treg cells secrete IL-10 and transforming growth factor-β (TGF-β) which suppress virus specific T cell responses[ 91 - 93 ]. CD4 + CD25 + Treg cells obtained from chronically HCV infected patients demonstrated greater suppressive activity against HCV specific CD8 + T cells compared to Treg cells isolated from acute HCV infected patients. However, the suppressive effect observed in patients who successfully cleared the virus was still significant[ 90 ]. Another study showed that the frequency of CD4 + CD25 + FoxP3 + Treg cells and their suppressive capacity against virus specific T cell responses were as high in HCV recovered chimpanzees as those in persistently HCV infected chimpanzees[ 94 ]. This observation requires further in-depth studies to explore the actual suppressive effect of Treg cells during HCV infection. Induction of Treg cells by HCV antigens was first demonstrated by the response of CD4 + T cell to HCV core protein. HCV-specific IL-10 secreting T cells were detected in the blood of chronic HCV infected persons[ 95 ]. Regulatory CD8+ T cells may play an important role in chronic HCV infection. HCV-specific CD8 + CD25 + FoxP3 + T cells from the blood of chronically infected patients suppress HCV-specific T cell responses via TGF-β secretion. The blockade of TGF-β markedly enhanced HCV specific IFN-γ secretion by CD4 + and CD8 + T cells[ 96 ].

Few other studies have shown that chronic HCV infection results in exhaustion or impairment of HCV-specific CD8 + T cells. During chronic HCV infection, CD8 + T cells fail to proliferate or secrete antiviral cytokines including IFN-γ. This phenomenon is promoted by a lack of CD4 + T cells and the expression of immunomodulatory cytokines such as IL-10[ 97 ]. The major cause of HCV-specific CD8 + T cell impairment is ascribed to the expression of inhibitory receptors such as Programmed death-1, lymphocyte-activation gene-3 (a protein related to CD4), CTLA-4 (a member of the CD28 receptor family), T-cell immunoglobulin mucin-3 and 2B4 on HCV-specific CD8 + T cells in blood and liver[ 98 ]. Expression of these inhibitory receptors is associated with low levels of CD127 expression and impaired proliferation and differentiation of T cells. Thus, different mechanisms contribute to the dysfunction of HCV-specific CD8 + T cells in chronic HCV infection.

In addition to cytotoxic T lymphocytes, humoral immune response against viral and cellular components during HCV infection is also present. Patients positive for HCV RNA and/or anti-HCV antibodies have type I anti-liver kidney microsome antibodies, which also recognize cytochrome P450 (CYP) 2D6. The patient’s liver is infiltrated with auto reactive mononuclear cells, which recognize CYP2D6. It is interesting that the viral core protein residues 178-187 bear sequence homology with human cytochrome P450 (CYP2A6 and CYP2A7) residues 8-17[ 96 ]. Although HCV is a hepatotropic virus and infects hepatocytes, viral genome and its replicative intermediates are frequently present in peripheral blood mononuclear cells and lymphoid tissues of chronically infected persons. The viral glycoprotein E2 has been implicated in the oligoclonal expansion of several lymphoma cells[ 99 ]. The most common rheumatic and cutaneomucous symptoms in HCV-infected patients include fatigue, arthralgia, paraestheisa, myalgia, pruritus, and the sicca syndrome[ 100 ].

ROLE OF VIRAL PROTEINS AND GENOTYPES

The role of structural and non-structural components of the HCV virion has been explained by variation in their interactions with metabolites affecting pathogenic pathways leading to liver damage. HCV-core protein has a prominent role in all these interactions as compared to envelope and non-structural proteins. Moreover, when the mechanism of this interaction was studied in relation to various HCV genotypes, it was observed that different genotypes behave differently to regulate all these pathogenic pathways.

The role of NS5A and E2 region was found be important. NS5A has a role in viral replication, inactivating PKR[ 101 - 104 ], blocking the apoptotic pathway, binding of growth factor receptor-bound protein 2[ 105 , 106 ] and induction of anti-inflammatory interleukin secretion[ 107 , 108 ]. Similarly, E2 protein inhibits PKR[ 109 , 110 ]. The region of NS5A which interacts with PKR, shows clustering of amino acid changes during IFN treatment and plays an important role in the evasion mechanism[ 111 ]. Furthermore, this association varies with genotype and thus, alters their sensitivity to IFN treatment. NS5A remains under strong immune selection, has T- and B-cell epitopes and possibly, in combination with individuals’ HLA, selects immune cells to produce sensitivity/resistance to IFN therapy[ 112 ]. The functional activity of NS5A towards immune selection is clearly governed by the HCV-genotypes and varies accordingly. The response of genotype 2 and 3 to IFN treatment may be due to individuals recognizing the NS5A protein immunologically[ 13 ].

Binding of HCV E2 protein to DCs induces their maturation. Several HCV viral proteins, including core, NS3, NS5A and NS5B proteins, have been shown to inhibit DC functions[ 69 ]. Consequently, the functions of both CD4 + Th cells and CD8 + CTLs are impaired in chronic HCV patients. This has been suggested to be one of the mechanisms that HCV utilizes to weaken host immune responses and spread the infection. Indeed, many clinical studies have shown that in chronic HCV patients, not only the functions of DCs are impaired[ 113 , 114 ], the functions of both CD4 + and CD8 + T cells are also impaired[ 115 ]. A similar inductive effect of E2 protein was also reported in other cell types, including T cells, B cells[ 116 ], hepatocytes[ 117 ] and hepatic stellate cells[ 118 ].

The role of HCV genotypes in the progression of liver disease is one of the most controversial areas of HCV research. In patients with chronic HCV, infection with genotype-1b is reportedly associated with a more severe liver disease and a more aggressive course than the infection with other HCV genotypes. Similarly, it was found that HCV genotype-1b was significantly more prevalent among patients with liver cirrhosis and those with decompensated liver disease requiring liver transplantation than among those with chronic active hepatitis C[ 119 - 121 ]. Although this is indirect evidence, it suggests an association between HCV genotype-1b and the development of these complications. HCV genotype-1b is a marker for more severe HCV associated liver disease, because it reflects a longer time of infection than a mere aggressive form of hepatitis C.

METABOLIC CONDITIONS AFFECTING HCV PATHOGENESIS

In addition to immune mediated HCV pathogenesis, there are several other clinical and metabolic conditions that have a strong association with HCV pathogenesis. These include HCV-induced insulin resistance, oxidative stress and hepatic steatosis. The following is a brief description of the conditions affecting HCV pathogens:

HCV-induced insulin resistance

HCV infection influences overall metabolism leading to increased steatosis, fibrosis, inflammation, apoptosis and insulin resistance (IR)[ 122 , 123 ] during the course of the disease. The resulting IR shows a modulating impact on liver pathogenesis by HCV infection[ 124 ]. IR increases the de novo lipogenesis i.e ., fatty acid (FA) synthesis via overexpression and maturation of SREBP-1c. This in turn, increases the activities of lipogenic enzymes including Acetyl CoA carboxylase and FA synthase. At the same time, intermediates of triglyceride biosynthesis also activate inhibitors of insulin signaling. For example, activation of protein kinase C-E by phosphorylating insulin receptor substrate, and thus inhibiting phosphatidyl inositol-3,4,5-triphosphate[ 125 ], inhibits Akt translocation by ceramides etc .[ 126 ]. HCV-core protein, either directly or via increased secretion of TNF-α, causes IR[ 127 , 128 ]. The HCV core can activate inhibitors of insulin signaling including mammalian target of rapamycin[ 129 ] and suppressor of cytokine signaling (SOCS)-3 and C-Jun N-terminal kinase (JNK)[ 130 , 131 ]. The activation of JNK by HCV core may follow a direct or indirect proinflammatory cytokine-mediated mechanism.

HCV-associated oxidative stress

Oxidative stress is reported to be an important part of HCV-induced liver damage. Previous studies investigated the role of different molecular components of HCV structure in modulating oxidative stress during HCV infection. HCV-core protein present within the outer membrane of mitochondria induces oxidation of glutathione and promotes Ca 2+ uptake into mitochondria. Clément et al[ 96 ] explained the molecular mechanism and demonstrated that following glutathione oxidation, there is increased reactive oxygen species (ROS) production by mitochondrial electron transport complex I and III. The HCV non-structural protein, NS5A, promotes ROS production in the membrane of endoplasmic reticulum (ER) by activating the release of Ca 2+ from ER, thereby inducing oxidative stress[ 97 ]. NS3 protein induces ROS production by activation of NADPH oxidase[ 97 ]. Increased ROS production and consequent oxidative stress is evident by the presence of markers of increased oxidative stress in the blood. Levels of 8-hydroxy deoxyguanosine and 4-hydroxy-2-nonenol are increased in HCV infection[ 132 , 133 ]. Similarly, few studies have shown reduced levels of glutathione during HCV infection. Another study showed that the serum level of thioredoxin, a marker of oxidative stress, was significantly reduced in HCV infection[ 134 - 136 ].

The presence of oxidative stress has been noted in different types of hepatitis including hepatitis B. However, there is a marked increase in oxidative stress (OS) in HCV infection[ 132 ]. Several studies have shown that structural components of HCV induce effective OS[ 132 ]. HCV-core and non-structural components, NS3 and NS5A proteins, directly induce OS[ 137 - 139 ]. Core protein is involved in OS generation via oxidation of mitochondrial glutathione and uptake of Ca 2+ into mitochondria[ 139 , 140 ] thus, changing the permeability of its membrane[ 141 ]. Electron transport complex I increases production of ROS and redistributes cytochrome from mitochondria to the cytosolic fraction[ 93 ]. NS5A is associated with the ER membrane[ 142 ] and activates signal transducer transcription and NFκB[ 107 ]. These activations lead to inflammation, immune response and apoptosis[ 143 ]. Similarly, NS3 triggers ROS by activating NADPH oxidase 2 in mononuclear and polymorphonuclear phagocytes[ 144 ] which increase apoptosis of hepatocytes[ 144 ]. All these reports conclude that the structural and non-structural components of HCV induce a significant increase in OS that results in liver damage during HCV infection.

HCV-induced steatosis

HCV infection is reported to have a strong association with hepatic steatosis. There are several other factors also responsible for steatosis, which include alcohol consumption, obesity, and diabetes[ 145 - 147 ]. Studies on steatosis in relation to hepatotropic viruses demonstrated that HCV infection directly causes steatosis in some patients[ 148 ]. Studies in experimental animals have shown that HCV-core protein promotes liver steatosis[ 149 , 150 ]. Furthermore, when steatosis was studied in relation to HCV-genotypes, it was noted that although steatosis is induced by all HCV-genotypes, it appears more prominent and frequent with HCV-genotype 3 infection[ 151 - 153 ]. In patients carrying genotype-3 infection, there was a good correlation between the level of steatosis and HCV replication[ 153 , 154 ] and the presence of HCV-core in the liver. In addition, steatosis resolves in patient with genotype-3 when treated successfully with anti-viral therapy as compared to those with non-genotype-3 who remain steatotic[ 155 , 156 ]. Steatosis reappears with relapse of infection[ 155 ]. This clearly demonstrates that some HCV-genotypes have more steatogenic potential. Subsequent studies[ 157 ] indicated that genotype-3 interferes with very low-density lipoprotein (VLDL) secretion. Core protein, which promotes lipid accumulation in hepatocytes[ 158 , 159 ], was more efficient from genotype-3 compared to core protein from genotype-1.

All these reports concluded that HCV causes steatosis in three different ways: (1) Impaired secretion of lipids from hepatocytes; (2) Increased de novo synthesis of free fatty acids (FFAs); and (3) Impaired FA degradation. The first aspect of HCV-induced steatosis was proposed due to the impaired secretion of VLDL. To substantiate this, reports from different studies demonstrated a decreased level of apolipoprotein B and cholesterol in chronic HCV infected patients[ 159 , 160 ]. These low levels pointed to HCV disturbing the assembly and secretion of VLDL from the liver[ 161 ]. Another important aspect in this relationship was increased de novo synthesis of FFAs in the presence of HCV infection. In this context, it is suggested that HCV upregulated the sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway[ 158 ] with NS2 and NS4B proteins inducing SREBP at the transcriptional level[ 162 , 163 ]. SREBP was also induced by expression of HCV core protein. Studies in chimpanzees infected with HCV also demonstrated that HCV increased the activity of lipogenic enzymes such as ATP citrate lyase[ 164 ]. HCV-core, in particular, activates and helps in cellular lipid synthesis[ 164 ], possibly via its binding with retinoid receptor.

HCV-induced steatosis is also due to impaired FA degradation by HCV. Expression of HCV-core protein is reported to reduce the expression of peroxisome proliferation activated receptor-α (PPARα), a nuclear receptor involved in FA degradation and down-regulation of mitochondria β-oxidation[ 165 ]. Genotype-3 shows significant down-regulation of PPARα as compared to genotype-1[ 166 , 167 ]. HCV-core protein also down-regulates PPARα and therefore, is more effective when from genotype-3 as compared to genotype-1. The core protein from genotype-3 also down-regulated the PPARγ and up-regulated SOCS-7 in human hepatoma cells[ 167 ]. These data clearly show that HCV-core protein may modulate the expression of various genes responsible for FA degradation via down-regulation of PPARs.

HCV infection, previously known as blood borne non-A, non-B infection, is a serious public health problem worldwide. The diagnosis of HCV is based on the detection of anti-HCV antibodies and/or viral nucleic acid in serum. Studies over the last few years have developed assays not only for the accurate serodiagnosis of infection, but also identification of HCV serotypes. The pathogenesis of HCV infection is quite complex and regulated by host immunity as well as several metabolic activities influencing liver function. Whereas both innate and adaptive immunity are involved in the pathogenic action of HCV, the cytotoxic lymphocytes are crucial in deciding the eradication or persistence of viral particles. Moreover, the persistence of HCV infection is also affected by viral proteins, HCV isotypes and liver metabolism. In order to understand HCV pathogenesis further investigations are needed.

ACKNOWLEDGMENTS

We thank and appreciate the financial aid provided by ICMR, New Delhi, India to conduct this study. We are also thankful to Mrs. Suman Rawat for preparing this manuscript.

P- Reviewer: Wang Y S- Editor: Ma YJ L- Editor: Webster JR E- Editor: Zhang DN