Chronic Hepatitis C

The hepatitis C virus (HCV) is one of the most important causes of chronic liver disease in the United States. It accounts for about 15% of acute viral hepatitis cases, 60% to 70% of chronic hepatitis cases, and nearly half of all cases of cirrhosis (scarring of the liver), end-stage liver disease, and liver cancer.

Symptoms


Chronic hepatitis C varies greatly in its course and outcome. Infected patients may show no signs or symptoms of liver disease and have completely normal serum liver enzyme levels (the blood test that measures liver activity or condition). In studies of people with chronic hepatitis C, some liver biopsy results show a mild degree of injury to the liver, and the overall prognosis may be good. At the other end of the spectrum are patients with severe hepatitis C who have symptoms, high levels of the virus in the bloodstream and elevated serum enzymes. They are likely to develop cirrhosis and end-stage liver disease. In the middle of the spectrum are many patients who have few or no symptoms, mild to moderate elevations in liver enzymes, and an uncertain prognosis.

Many people with chronic hepatitis C have no symptoms of liver disease. If symptoms are present, they are usually mild, nonspecific, and intermittent. They may include the following


 * fatigue
 * mild discomfort or tenderness in the right upper abdomen (where the liver is located)
 * nausea
 * poor appetite
 * muscle and joint pains
 * itching of the skin (with jaundice)

Similarly, the physical exam is likely to be normal or show only tenderness or mild enlargement of the liver. In cases of liver failure, patients may show characteristic signs, some of which include bleeding, fluid collection in the abdomen (ascites), hemorrhoids, and a redness color to the palms of the hands.

Clinical features of cirrhosis
Once a patient develops cirrhosis (scarring of the liver) or if the patient has severe disease, symptoms and signs are more prominent. In addition to fatigue, the patient may complain of muscle weakness, poor appetite, nausea, weight loss, itching, dark urine, fluid retention, and abdominal swelling.

Below are some physical findings of cirrhosis:


 * enlarged liver
 * enlarged spleen
 * jaundice (yellowing of the skin and whites of the eyes)
 * muscle wasting
 * scratches or abrasions on the skin
 * fluid-filled abdomen (ascites)
 * ankle swelling (edema)
 * prominent veins on the abdomen

Cause
Chronic Hepatitis C represents a late-stage development in people who are infected with the hepatitis C virus. HCV was identified in 1989. Viral hepatitis not due to hepatitis A or B virus had been known since the 1970s. It was originally called non-A, non-B hepatitis.

Unlike the other types of viral hepatitis, it is very difficult for the immune system to rid HCV from the body. As a result, most hepatitis C infections (80%–90%) become chronic and lead to cirrhosis, liver failure, or other liver diseases.

The viruses that cause hepatitis C can have different genetic makeups, or genotypes. At least six major genotypes and more than 50 subtypes exist. The different genotypes have different geographic distributions. Genotypes 1a and 1b are the most common in the United States (about 75% of cases). Genotypes 2 and 3 are present in only 10 to 20% of patients. There is little difference in the severity of disease or outcome of patients infected with different genotypes. However, patients with genotypes 2 and 3 are more likely to respond to treatment with interferon.

Diagnosis
See also Hepatitis C.

Initial screenings for HCV look for antibodies in the blood directed against HCV and for signs of liver damage (elevated liver enzymes) that have persisted for more than six months. Antibodies are detected in a test called an enzyme immunoassay (EIA). The third-generation test (EIA-3) used today is more sensitive and specific than previous ones. As with all enzyme immunoassays, however, false-positive results are occasionally a problem (the test is positive but the person does not have the disease). Antibodies are present in almost all infections after one month from the time of exposure.

Polymerase chain reaction (PCR) and transcription-mediated amplification (TMA) techniques are used to confirm a hepatitis C diagnosis. These methods detect viral RNA (ribonucleic acid, the viral genetic material) in the blood. The presence of HCV RNA in serum indicates an active infection. These tests can detect viral RNA in almost all infected patients. Testing for HCV RNA is also helpful in patients in whom EIA tests for anti-HCV antibodies are unreliable. For instance, patients with a suppressed immune system may test negative for anti-HCV antibodies despite having HCV infection. This is because they may not produce enough antibodies for detection with EIA. Likewise, patients with acute hepatitis may test negative for anti-HCV when first tested. Tests that detect viral RNA will also detect acute infection that occurs before antibodies are produced.

People with a suppressed immune system may not be able to produce antibodies to the virus. These patients include solid-organ transplant recipients, those undergoing dialysis, those taking corticosteroids, or those with agammaglobulinemia. In these cases, tests for anti-HCV antibodies do not detect the virus. Instead, PCR is used to detect viral RNA

Diagnosis can be confounded in cases where anti-HCV antibodies are present, but the liver damage is not caused by the virus. Some people who have liver disease from alcoholism, iron overload, autoimmune disorders or other conditions, may also be infected with HCV. Their antibody blood test will be positive, but in these cases, the HCV is not the cause of the liver damage. Thus, a positive anti-HCV antibody test in a person with chronic liver disease does not always mean that HCV is the culprit. Further blood tests and possibly a biopsy of the liver may be needed to distinguish one cause from another.

Recombinant immunoblot assay
Immunoblot assays can be used to confirm the presence of anti-HCV antibodies. These tests are also known as Western blots. Immunoblotting is helpful in many clinical situations. For example, it can confirm the diagnosis in patients who test positive for antibodies, but who also test negative for HCV RNA. In addition, immunoblotting can determine if a positive antibody test is a false-positive. If immunoblotting is negative for the virus, the EIA result was indeed a false-positive.

Immunoblot tests are routine in blood banks when an anti-HCV-positive sample is found by EIA. Immunoblot assays are highly specific and valuable in verifying anti-HCV reactivity. Indeterminate tests require further follow-up testing, including attempts to confirm the specificity by repeat testing for HCV RNA.

Direct assays for HCV RNA
PCR and TMA amplification can detect low levels of HCV RNA in serum. Testing for HCV RNA is a reliable way of demonstrating that hepatitis C infection is present and is the most specific test for infection. This test is particularly useful when hepatitis C infection is suspected, but liver enzyme levels are normal or only slightly elevated, or when anti-HCV antibodies are not present, or when several causes of liver disease are possible.

Biochemical indicators of infection
Liver cells release enzymes into the blood when they are damaged by disease, including hepatitis C infection. Laboratory tests can be used to detect these enzymes in a blood sample. However, many diseases and conditions cause similar elevated enzyme levels, and these enzymes can come from other organs besides the liver. Therefore, these biochemical markers are not specific for HCV infection. Enzymes that indicate damage by HCV include alanine and aspartate aminotransferases. Up to 40% of patients with chronic hepatitis C have normal serum alanine aminotransferase levels, even when tested on multiple occasions.

Other laboratory findings can suggest liver damage or infection by HCV. Low numbers of platelets and white blood cells with increased levels of proteins called immunoglobulins suggest severe fibrosis or cirrhosis.

Quantification of HCV RNA in serum
Several methods are available for measuring the concentration or level of virus in serum, which is an indirect assessment of viral load. These methods include a quantitative PCR and a branched DNA (bDNA) test. Unfortunately, these assays are not well standardized, and different methods from different laboratories can provide different results on the same specimen. In addition, serum levels of HCV RNA can vary spontaneously by 3- to 10-fold over time. Nevertheless, when performed carefully, quantitative assays provide important insights into the nature of hepatitis C. Most patients with chronic hepatitis C have levels of HCV RNA (viral load) between 100,000 and 10,000,000 copies per mL. Expressed as International Units (IU), these averages are 50,000 to 5 million IU.

Viral levels as measured by HCV RNA do not correlate with the severity of the hepatitis or with a poor prognosis (as in HIV infection); but viral load does correlate with the likelihood of a response to antiviral therapy. Rates of response to a course of peginterferon (Roferon) and ribavirin (Rebetol) are higher in patients with low levels of HCV RNA (usually defined as below 800,000 IU [approximately 2 million copies] per ml).

In addition, monitoring HCV RNA levels during the early phases of treatment may provide information on the likelihood of a response. Yet because of the shortcomings of the current assays for HCV RNA level, these tests are not always reliable guides to therapy.

Genotyping and serotyping of HCV
Viral genotypes help define the prevalence of hepatitis C. But more important, knowing the genotype or serotype (genotype-specific antibodies) of HCV helps guide treatment. Patients with genotypes 2 and 3 are two to three times more likely to respond to interferon-based therapy than patients with genotype 1. Furthermore, when using combination therapy, the recommended dose and duration of treatment depend on the genotype. For these reasons, testing for HCV genotype is clinically important. Once the genotype is identified, it need not be tested again; genotypes do not change during the course of infection.

Liver biopsy
A liver biopsy is not necessary for diagnosis, but it helps grade the disease severity and stage the amount of liver damage. Necrosis, Fibrosis, and inflammation are detected with special stains that can be seen under a microscope.

Liver biopsy is also helpful in ruling out other causes of liver disease, such as alcoholic liver injury, nonalcoholic fatty liver disease, or iron overload.

HCV causes inflammation and cells to die (necrosis) in several regions of the liver. Inflammation and necrosis can be graded as none, minimal, mild, moderate, or severe. Fibrosis of the liver is staged using different scales. One common classification is a scale from 0 to 4 where stage 0 indicates no fibrosis; stage 1 indicates enlargement of the portal areas by fibrosis; stage 2 indicates fibrosis extending out from the portal areas with rare bridges between portal areas; stage 3 indicates many bridges of fibrosis that link up portal and central areas of the liver; and stage 4 indicates cirrhosis.

Noninvasive tests
While liver biopsy is considered the gold standard for assessing the severity of liver disease, it is not always accurate and has several shortcomings. Liver biopsy can under- or over-estimate the severity of hepatitis C, particularly if the biopsy is small, or if the specimen is read by an inexperienced pathologist. In addition, liver biopsy is an invasive procedure that is expensive and not without complications. At least 20% of patients who undergo a liver biopsy have pain that requires medications. Rare complications include puncture of another organ, infection, and bleeding. Significant bleeding after liver biopsy occurs in one out of 100 to one out of 1,000 cases, and deaths are reported in one out of 5,000 to one out of 10,000 cases. Given these statistics, noninvasive means of grading and staging liver disease would be very helpful.

Levels of the enzyme alanine transaminase, particularly if tested over an extended period, are reasonably accurate reflections of disease activity. Thus, patients with repeatedly normal alanine transaminase levels usually have mild inflammation and liver cell injury on liver biopsy. Furthermore, patients who maintain alanine transaminase levels above five times the upper limit of normal usually have marked inflammatory activity. But for the majority of patients with mild to moderate alanine transaminase elevations, the actual level is not very predictive of liver biopsy findings.

More importantly, methods other than liver biopsy need to be developed that stage liver disease and measure fibrosis. Unfortunately, serum tests are not reliable in predicting fibrosis, particularly earlier stages (0, 1, and 2). When patients develop bridging (stage 3) fibrosis and cirrhosis (stage 4), serum tests may be helpful. The danger signals that suggest the presence of advanced fibrosis include an aspartate aminotransferase that is higher than alanine transaminase, elevations in other enzymes, a decrease in platelet count, and elevations in proteins called globulins.

Differential diagnosis
Several conditions can be confused with hepatitis C:


 * autoimmune hepatitis
 * chronic hepatitis B and D
 * alcoholic hepatitis
 * nonalcoholic steatohepatitis (fatty liver)
 * sclerosing cholangitis
 * Wilsons disease
 * alpha-1-antitrypsin-deficiency-related liver disease
 * drug-induced liver disease

Treatment
The Centers for Disease Control and Prevention (CDC) has compiled guidelines for the management and treatment of chronic hepatitis C. These guidelines are based on published research summarized below.

Alpha interferon
The therapy for chronic hepatitis C has evolved steadily since alpha interferon was first approved for use in this disease more than 10 years ago. At the present time, the optimal regimen is a 24- or 48-week course of the combination of pegylated alpha interferon and ribavirin.

Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. Recombinant forms of alpha interferon have been produced, and several formulations (alfa-2a, alfa-2b, consensus interferon) are available as therapy for hepatitis C. These standard forms of interferon, however, are now being replaced by pegylated interferon (peginterferon).

Ribavirin
Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV; but adding it to interferon increases the sustained response rate by two- to three-fold. For these reasons, combination therapy is now recommended for hepatitis C, and interferon as a single therapy is used only when there are specific reasons not to use ribavirin.

Combination Therapy
Combination therapy eliminates detectable HCV RNA in up to 70% of patients. Among patients who become HCV RNA negative during treatment, some will relapse when therapy is stopped. The relapse rate is lower in patients treated with combination therapy compared with monotherapy.

For patients with genotypes 2 and 3, a 24-week course of combination treatment using peginterferon and 800 milligrams (mg) of ribavirin daily is adequate, whereas for patients with genotype 1, a 48-week course and full dose of ribavirin (1,000 to 1,200 mg daily) is recommended.

There is little information on the optimal regimen of peginterferon and ribavirin for patients with the rare genotypes 4, 5, and 6. These patients should probably receive the regimen of peginterferon and ribavirin that is recommended for genotype 1.

Many attempts have been made to identify patients who have a rapid response to treatment and who might be able to stop peginterferon and ribavirin early and be spared the further expense and side effects of prolonged therapy. Patients who test HCV RNA negative within 4 weeks of starting therapy are considered “rapid responders.” In several studies, rapid responders with genotypes 2 and 3 have been found to be able to stop therapy after 12 to 16 weeks (12 to 8 weeks early) and still achieve a high rate of response. Similarly, rapid responders with genotype 1 may be able to stop therapy at 24 weeks (24 weeks early) and achieve an excellent response rate. The consequence of early discontinuation, however, is a higher relapse rate and this approach of abbreviating therapy in rapid responders must be individualized based upon tolerance.

Treatment Eligibility
The combination of peginterferon and ribavirin is typically given to people who have 1) anti-HCV antibodies, HCV RNA, and elevated serum aminotransferase levels in the blood, 2) evidence of chronic hepatitis on liver biopsy, and 3) no reason they cannot receive the combination (contraindications). The National Institutes of Health Consensus Development Conference Panel recommended that therapy for hepatitis C be limited to those patients who show progressive damage to the liver. Thus, the panel recommended that all patients with fibrosis or moderate to severe disease be treated, and that patients with less severe damage be managed on an individual basis. Patient selection should not be based on the presence or absence of symptoms, the mode of acquisition, the genotype of HCV, or serum HCV RNA levels.

Patients with cirrhosis are often treated. However, combination therapy has not been shown to improve survival or the ultimate outcome in patients with pre-existing cirrhosis.

The role of peginterferon and ribavirin therapy in children with hepatitis C remains uncertain. Ribavirin has yet to be evaluated adequately in children, and pediatric doses and safety have not been established. Thus, if children with hepatitis C are treated, monotherapy is recommended.

People with both HCV and HIV infection should be offered therapy for hepatitis C as long as there are no contraindications. Indeed, hepatitis C tends to be more rapidly progressive in patients with HIV co-infection, and end-stage liver disease has become an increasingly common cause of death in HIV-positive people. For these reasons, HIV-infected patients often receive treatment for hepatitis C.

Antiviral therapy is effective in 70%–80% of individuals with genotypes 2 and 3 and 40%–55% in patients with genotype 1. Several factors influence the outcome of therapy:


 * Viral load&mdash;response rates are higher if HCV RNA levels are low.


 * Gender&mdash;women respond better than men.


 * Age&mdash;younger people respond better than older.


 * Weight&mdash;people with normal weight respond better than those who are overweight.


 * Degree of fibrosis&mdash;people with more fibrosis or scarring of the liver have a poorer response.


 * Race&mdash;Caucasians and Asians respond better than African Americans. Response rates in African Americans with genotype 1 can be as low as 25%–30%.

In people whose disease has spread beyond the liver to cause conditions such as cryoglobulinemia (see “Complications") and kidney inflammation, therapy with interferon can result in remission of the clinical symptoms and signs. However, relapse after stopping therapy is common. In some patients, long-term or maintenance peginterferon therapy can be used despite persistence of HCV RNA in serum if clinical symptoms and signs resolve on therapy.

Ineligible patients
Therapy is inadvisable outside of controlled trials for patients who have the following:


 * cirrhosis
 * kidney, liver, heart, or other solid-organ transplant
 * specific contraindications to either monotherapy or combination therapy (e.g., depression, drug abuse, and arthritis or other autoimmune diseases)

Side effects of treatment
Common side effects of alpha interferon and peginterferon (occurring in more than 10% of patients) include the following:


 * fatigue
 * muscle aches
 * headaches
 * nausea and vomiting
 * skin irritation at the injection site
 * low-grade fever
 * weight loss
 * irritability
 * depression
 * mild bone marrow suppression
 * hair loss (reversible)

Most of these side effects are mild to moderate in severity and can be managed. They are worse during the first few weeks of treatment, especially with the first injection. Thereafter, side effects diminish. Acetaminophen (Tylenol) or a non-steroidal anti-inflammatory drug {NSAID) such as ibuprofen (Advil, Motrin) or naproxen (Naprosyn, Aleve) may be helpful for the muscle aches and low-grade fever. Fatigue and depression are occasionally so troublesome that treatment is stopped.

Ribavirin also causes side effects, and the combination is generally less well tolerated than peginterferon monotherapy. Below are some of the most common side effects of ribavirin:


 * anemia
 * fatigue and irritability
 * itching
 * skin rash
 * nasal stuffiness, sinusitis, and cough

Ribavirin can also destroy red blood cells and cause anemia.

Other treatment options
Few options exist for people who either do not respond to therapy or who respond and later relapse. People who relapse after a course of interferon or peginterferon monotherapy may respond to a course of peginterferon and ribavirin combination therapy, particularly if they became and remained HCV RNA negative during the period of monotherapy. The response rates and optimal dose and duration of peginterferon and ribavirin for relapse or previous nonresponder patients have not been defined.

Prevention
Several measures can be taken by an infected individual to reduce the risk of spread to others:


 * Avoiding donating blood, organ, semen, or other tissues.
 * Do not share personal items that might have blood on them.
 * Cover cuts and skin sores.

Several measures can be taken to reduce the risk of catching HCV:


 * Avoid intravenous drug use.
 * Do not share toothbrushes, razors, or other personal care articles. They might have blood on them.
 * Healthcare workers can follow routine barrier precautions and safely handle needles and other sharps.
 * Avoid tattoos and body piercing as these procedures carry some risk.

HCV can be spread by sex. The effectiveness of latex condoms and spermicides for prevention of infection is not known.

Living with
Several lifestyle modifications can improve the quality of life of people with HCV. The U.S. National Hepatitis C Program has outlined several lifestyle modifications to help people live with the chronic HCV. The following information is from their web site.

Diet and nutrition
Nutrition refers to everything that happens in the body after consumption of food. This includes food moving through the stomach and intestines, where it gets broken down into smaller units called "nutrients." Nutrients include fats, proteins, carbohydrates, vitamins, minerals, and water.

All food is passed through the liver. The liver changes food into stored energy and chemicals necessary for life. It makes nutrients available so your body can use them to build cells, provide energy, and maintain normal body functions.

A bad diet sometimes can lead to liver problems. A diet of too many calories causes weight gain. Fatty liver results from too much weight gain. Over many years, fatty liver probably contributes to a person with hepatitis C developing cirrhosis. Being overweight and having fatty liver also have been shown in a number of studies to lead to lower rates of hepatitis C clearance in patients treated with interferon and ribavirin.

One's diet also can contain toxins that are harmful to the liver. Some toxins act quickly. Eating certain poisonous mushrooms, for example, can cause liver failure and death within days. Other toxins, such as alcohol, damage the liver over time.

A good diet, by contrast, can improve liver health in a person with hepatitis C. A balanced diet can lead to better liver functioning and lowered risk of cirrhosis (scarring) of the liver. It also can help the immune system stay strong and fight off illness.

Finally, people infected with hepatitis C have higher rates of diabetes than those who are not infected, but a good diet can help reduce body fat and control blood sugar. This lowers diabetes risk.

People with hepatitis don’t necessarily need a special diet. A healthy diet will help reduce the risk of complications.

Hepatitis C infection can affect diet. Treatment too can affect appetite and diet. Treatment with interferon sometimes causes loss of appetite, sore mouth and throat, metallic tastes, nausea, and vomiting. Diet modifications may help reduce these effects. Cirrhosis often causes loss of appetite and fatigue that discourages eating. In some cases, severe weight loss and malnutrition result.

Eating healthy and often can help prevent the nausea caused by some hepatitis medications.

Weight-induced problems can be reversed. Losing weight and keeping the weight off can improve liver enzyme levels and fibrosis.

Avoid fad diets, because losing weight too fast can put strain on the liver.

Exercise is important, and not just because it helps keep weight down. Exercise can improve appetite, relieve some of the side effects of hepatitis C medications, boost the immune system, and improve the sense of well-being.

Remember that patients with cirrhosis can put on "fluid weight." This is different from "fat weight," which is what most of us put on. Fluid weight is managed in a different way.

At present, there is no evidence for a safe level of alcohol for people with hepatitis C. The best advice is to avoid alcohol completely.

Vitamin and mineral supplements
Some people with hepatitis C, particularly those with cirrhosis, have above-average levels of iron in their body. Too much iron can damage organs. If these people take multivitamin/mineral pills, they should take the ones without iron. These pills usually are marketed as formulas for men or adults over 50. These people also should avoid taking large doses of vitamin C because vitamin C helps the body absorb iron.

Vitamin A, if taken in doses larger than the recommended 10,000 IU, can harm the liver. Vitamin A is even more toxic in someone who drinks alcohol. Some dietary supplements have high amounts. Many fruits and vegetables contain beta carotene, a non-toxic form of vitamin A. Some supplements also contain this form of vitamin A.

Herbal products
Just because something is "natural" doesn't mean it is harmless. Certain herbs, including Kava-Kava and pennyroyal, can cause liver damage.

Calories and protein
People with cirrhosis may need more extra calories and protein. They may lose their appetite and experience nausea, vomiting, and severe weight loss. This can lead to shortage of the minerals calcium and magnesium (signs include muscle cramps, fatigue, weakness, nausea, and vomiting), or a shortage of zinc (signs include reduced ability to taste, changes in taste).

It can help to eat small, frequent meals (4 to 7 times a day), including an evening snack.

When the scarring from cirrhosis prevents blood from passing through the liver, pressure increases in the veins entering the liver. This is called portal hypertension. The body is forced to reroute the blood away from the liver and into the general blood circulation. This causes large blood vessels, called "varices," to form.

Because the rerouted blood bypasses the liver, it contains high levels of amino acids, ammonia, and toxins that normally would have been handled by the liver. When these substances reach the brain, they can cause confusion and temporary loss of memory (a condition called "hepatic encephalopathy").

Amino acids and ammonia come from protein in the diet. Some evidence shows that patients with cirrhosis do better when they get their protein from vegetables (such as beans, lentils, and tofu) and from dairy products (eggs, milk, yogurt) instead of from meats.

Doctors can prescribe a syrup called Lactulose to push food through the bowels more quickly. This way, less food is absorbed, the liver has less work to do, and fewer toxins make their way to the brain.

How is Spread
Hepatitis C is the most common blood borne infection in the United States, where 1.6%, or an estimated 4.1 million people, have antibody to HCV (anti-HCV). This indicates ongoing or previous infection with the HCV. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. About 75%–85% of people with acute hepatitis C ultimately develop chronic infection.

Risk factors and transmission


HCV is spread primarily by contact with infected blood and blood products. Blood transfusions and the use of shared, unsterile, or poorly sterilized needles, syringes and injection equipment or paraphernalia have been the main routes of the spread of HCV in the United States. With the introduction in 1991 of routine blood screening for HCV antibody in blood donors and improvements in the test in mid-1992, transfusion-related hepatitis C has virtually disappeared. At present, injection drug use is the most common risk factor for contracting the infection. However, some patients who acquire hepatitis C do not have a recognized risk factor or known exposure to infected blood or to drug use.

Other risk factors for HCV infection include:


 * receiving a blood transfusion before June 1992, when sensitive tests for anti-HCV antibody were introduced for blood screening
 * receiving clotting factor concentrates (such as anti-hemophilic factor) before 1987, when effective means to inactive HCV were introduced
 * undergoing hemodialysis for kidney failure
 * suffering a needle puncture from a person with hepatitis C

Sex with someone with hepatitis C, multiple sex partners, and intranasal use of cocaine with shared equipment have a smaller risk of transmitting infection.

Maternal-Infant transmission
Maternal-infant transmission is not common. In most studies, less than 5% of infants born to HCV-infected mothers become infected. The disease in newborns is usually mild and free of symptoms. The risk of maternal-infant spread rises with the amount of virus in the mother’s blood, if the mother also has human immunodeficiency virus (HIV) infection, or if there are complications of delivery such as early rupture of membranes, then the risk of transmission may be higher. Breast-feeding has not been linked to the spread of HCV to the newborn.

Sexual transmission
Sexual transmission of hepatitis C between monogamous partners is uncommon. Surveys of spouses and monogamous sexual partners of patients with hepatitis C show that fewer than 5% are infected with HCV, and many of these have other risk factors for this infection. Spread of hepatitis C to a spouse or partner in stable, monogamous relationships occurs in less than 1% of partners per year. For these reasons, changes in sexual practices are not recommended for monogamous patients. Testing sexual partners for anti-HCV can help with patient counseling.

Sporadic transmission
Sporadic transmission, when the source of infection is unknown, is the basis for about 10% and 30% of acute and chronic hepatitis C cases, respectively. These cases are usually referred to as sporadic or community-acquired infections. These infections may have come from exposure to the virus from cuts, wounds, or medical injections or procedures.

Unsafe injection practices
In many areas of the world, unsafe injection practices in the delivery of health care are an important and common cause of hepatitis C transmission (and hepatitis B as well). Use of inadequately sterilized equipment, reuse of needles and syringes, and inadvertent contamination of medical infusions are unfortunately well-documented causes of spread of hepatitis C. Careful attention to universal precautions and injection techniques should prevent this type of spread. In the United States, multiple-use vials are a frequent culprit in leading to medical-care linked spread of hepatitis C.

Complications in other organ systems
Complications in parts of the body other than the liver develop in 1%–2% of people with hepatitis C infection; the most common is cryoglobulinemia. Cryoglobulinemia is characterized by a cluster of conditions:


 * skin rashes
 * joint and muscle aches
 * kidney disease
 * abnormal sensations in the limbs (neuropathy)
 * cryoglobulins, rheumatoid factor, and low-complement levels in serum

Inflammation in the kidney (glomerulonephritis) and porphyria cutanea tarda are some other common complications of chronic hepatitis C.

Some other diseases are thought to be related to hepatitis C infection:


 * some forms of arthritis
 * Sjögren's syndrome
 * non-Hodgkin's type, B-cell lymphomas
 * fibromyalgia
 * lichen planus (small, discolored bumps on the skin)

Chronic hepatitis C infection can cause cirrhosis, liver failure, and liver cancer. Approximately 20% of patients with chronic hepatitis C develop cirrhosis, which takes 10 to 20 years to develop. Liver failure from chronic hepatitis C is one of the most common reasons for liver transplants in the United States. After 20 to 40 years, a small percentage of patients develop liver cancer. Hepatitis C is the cause of about half of cases of primary liver cancer in the developed world. Men, alcoholics, patients with cirrhosis, people over age 40, and those infected for 20 to 40 years are at higher risk of developing HCV-related liver cancer.

Clinical Trials
Given the scope of the hepatitis C problem, there are hundreds of clinical trials involving HCV and chronic hepatitis. See Chronic Hepatitis C for details.

Research
A major focus of hepatitis C research has been to develop a tissue culture system that will enable researchers to study HCV outside the human body. This goal was achieved in part in 2005 when three different laboratories reported tissue culture systems using HCV, genotype 2. These systems are now being improved and used to study how the virus infects cells and whether spread can be blocked by antibodies and by different antiviral drugs. Animal models and molecular approaches to the study of HCV are also important. Understanding how the virus replicates and how it injures cells would be helpful in developing a means of controlling it and in screening for new drugs that would block it.

Diagnostic tests
More sensitive and less expensive assays for measuring HCV RNA and antigens in the blood and liver are needed. Although current tests for anti-HCV are quite sensitive, a small percentage of patients with hepatitis C test negative for anti-HCV (false-negative reaction), and a percentage of patients who test positive are not infected (false-positive reaction). Also, there are patients who have resolved the infection but still test positive for anti-HCV. Convenient tests to measure HCV in serum and to detect HCV antigens in liver tissue would be helpful.

Recently, x-ray and imaging studies have been developed that may be able to separate different degrees of fibrosis in the liver. At present, these techniques are experimental and of unproven accuracy, particularly in detecting early stages of fibrosis. The most promising technique is elastrography, in which sound or magnetic waves are passed through the liver and the speed with which they return is measured. This provides an index of the elasticity and stiffness of the liver. Liver stiffness is used as an indirect measure of liver fibrosis. Most importantly, measuring the relative stiffness of the liver over time may provide a noninvasive way to monitor the development of fibrosis and help guide treatment. Ultrasound elastrography is currently under evaluation for its reliability in measuring the degree of fibrosis in the liver in patients with hepatitis C. Ultimately, elastrography may be able to replace liver biopsy as a way of monitoring the progression of disease in chronic hepatitis C.

New treatments
Most critical is the development of new antiviral agents. Promising drugs inhibit enzymes that are specific to the virus, such as protease, helicase, and polymerase. Drugs that inhibit steps in HCV replication may also be helpful in treating this disease by blocking production of HCV antigens from the RNA (IRES inhibitors), preventing the normal processing of HCV proteins (inhibitors of glycosylation), or blocking entry of HCV into cells (by blocking its receptors). Further, molecular approaches to treating hepatitis C are worthy of investigation; these consist of using ribozymes, which are enzymes that break down specific viral RNA molecules, and antisense oligonucleotides, which are small complementary segments of DNA that bind to viral RNA and inhibit viral replication. The serious nature and the frequency of hepatitis C in the population make the search for new therapies of prime importance.

Novel uses of existing drugs are also being investigated. An experimental approach to treatment of nonresponders is the use of long-term or maintenance peginterferon. This approach is now under evaluation in long-term clinical trials in the United States.

Prevention
At present, the only means of preventing new cases of hepatitis C are to screen the blood supply, encourage health professionals to take precautions when handling blood and body fluids, and inform people about high-risk behaviors. Programs to promote needle exchange offer some hope of decreasing the spread of hepatitis C among injection drug users. Furthermore, all drug users should receive instruction in safer injection techniques—simple interventions that can be life-saving. Vaccines and immunoglobulin products do not exist for hepatitis C, and development seems unlikely in the near future because these products would require antibodies to all the genotypes and variants of hepatitis C. Nevertheless, advances in immunology and innovative approaches to immunization make it likely that some form of vaccine for hepatitis C will eventually be developed.

Hepatitis C Information Central offers a web feed of recent news in research on chronic Hepatitis C.