Current Disease Management
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 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis-stage liver disease, and liver cancer. Of the U.S. population, 1.6 percent, or an estimated 4.1 million Americans, have antibody to HCV (anti-HCV), indicating ongoing or previous infection with the virus. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States.
A distinct and major characteristic of hepatitis C is its tendency to cause chronic liver disease in which the liver injury persists for a prolonged period if not for life. About 75 percent of patients with acute hepatitis C ultimately develop chronic infection.
Chronic hepatitis C varies greatly in its course and outcome. At one end of the spectrum are infected persons who have no signs or symptoms of liver disease and have completely normal levels of serum enzymes, the usual blood test results that indicate liver disease. Liver biopsy usually shows some degree of injury to the liver, but the extent is usually mild, 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 (HCV RNA) in serum, and elevated serum enzymes, and who ultimately 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.
Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. Researchers estimate that at least 20 percent of patients with chronic hepatitis C develop cirrhosis, a process that takes at least 10 to 20 years. 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.
Risk Factors and Transmission
HCV is spread primarily by contact with infected blood and blood products. Blood transfusions and the use of shared, unsterilized, 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 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.
The most common risk factors for acquiring hepatitis C are:
injecting drugs, including having used injection drugs only once many years ago
having a blood transfusion before June 1992, when sensitive tests for anti-HCV were introduced for blood screening
eceiving clotting factor concentrates (such as anti-hemophilic factor) before 1987, when effective means to inactive HCV were introduced
hemodialysis for kidney failure
birth to an HCV-infected mother
suffering a needle-stick accident from a person with hepatitis C
Other risk factors that have a slightly increased risk for hepatitis C are
having sex with someone with hepatitis C or having multiple sex partners
intranasal use of cocaine using shared equipment or paraphernalia
Maternal-infant transmission is not common. In most studies, less than 5 percent 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 and fetal monitoring. Breast-feeding has not been linked to the spread of HCV.
Sexual transmission of hepatitis C between monogamous partners appears to be uncommon. Surveys of spouses and monogamous sexual partners of patients with hepatitis C show that fewer than 5 percent 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 percent 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. People with multiple sex partners should be advised to follow safe sex practices, which should protect against hepatitis C as well as hepatitis B, HIV, and other sexually transmitted diseases.
Sporadic transmission, when the source of infection is unknown, is the basis for about 10 percent of acute hepatitis C cases and for 30 percent of chronic hepatitis C cases. 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 (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 transmission 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.
The Hepatitis C Virus
HCV is a small (40 to 60 nanometers in diameter), enveloped, single-stranded RNA virus of the family Flaviviridae and genus hepacivirus. Because the virus mutates rapidly, changes in the envelope proteins may help it evade the immune system. There are at least six major genotypes and more than 50 subtypes of HCV. The different genotypes have different geographic distributions. Genotypes 1a and 1b are the most common in the United States (about 75 percent of cases). Genotypes 2 and 3 are present in only 10 to 20 percent 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 interferon treatment.
Clinical Symptoms and Signs
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
mild right-upper-quadrant discomfort or tenderness (“liver pain”)
muscle and joint pains
Similarly, the physical exam is likely to be normal or show only mild enlargement of the liver or tenderness. Some patients have vascular spiders or palmar erythema.
Clinical Features of Cirrhosis
Once a patient develops cirrhosis 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.
Physical findings of cirrhosis may include
excoriations (scratches or abrasions on the skin)
ascites (fluid-filled belly)
Complications that do not involve the liver develop in 1 to 2 percent of people with hepatitis C; the most common is cryoglobulinemia, which is marked by
skin rashes, such as purpura, vasculitis, or urticaria
joint and muscle aches
cryoglobulins, rheumatoid factor, and low-complement levels in serum
Other complications of chronic hepatitis C areglomerulonephritis
porphyria cutanea tarda
Diseases that are less well documented to be related to hepatitis C are
keratoconjunctivitis sicca (Sjögren’s syndrome)
non-Hodgkin’s type, B-cell lymphomas
Persons suspected to have hepatitis C should be tested for anti-HCV as an initial screening test. Anti-HCV is detected by 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 with the EIA-3. Additional or confirmatory testing is often helpful.
The best approach to confirm the diagnosis of hepatitis C is to test for HCV RNA using a sensitive assay such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA). The presence of HCV RNA in serum indicates an active infection.
Testing for HCV RNA is also helpful in patients in whom EIA tests for anti-HCV are unreliable. For instance, immunocompromised patients may test negative for anti-HCV despite having HCV infection 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. Antibody is present in almost all patients by 1 month after onset of acute illness; thus, patients with acute hepatitis who initially test negative may need follow-up testing. In these situations, HCV RNA is usually present and confirms the diagnosis.
Recombinant Immunoblot Assay
Immunoblot assays can be used to confirm anti-HCV reactivity. These tests are also called “Western blots”; serum is incubated on nitrocellulose strips on which four recombinant viral proteins are blotted. Color changes indicate that antibodies are adhering to the proteins. An immunoblot is considered positive if two or more proteins react and is considered indeterminate if only one positive band is detected. In some clinical situations, confirmatory testing by immunoblotting is helpful, such as for the person with anti-HCV detected by EIA who tests negative for HCV RNA. The EIA anti-HCV reactivity could represent a false-positive reaction, recovery from hepatitis C, or continued virus infection with levels of virus too low to be detected (the last occurs only rarely when sensitive PCR or TMA assays are used). If the immunoblot test for anti-HCV is positive, the patient has most likely recovered from hepatitis C and has persistent antibody. If the immunoblot test is negative, the EIA result was probably 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. Testing for HCV RNA is particularly useful when aminotransferase levels are normal or only slightly elevated, when anti-HCV is not present, or when several causes of liver disease are possible. This method also helps diagnose hepatitis C in people who are immunosuppressed, have recently had an organ transplant, or have chronic renal failure. Currently available PCR assays will detect HCV RNA in serum down to a lower limit of 50 to 100 copies per milliliter (mL), which is equivalent to 25 to 50 international units (IU). A slightly more sensitive TMA test has recently become available. Almost all patients with chronic hepatitis C will test positive by these assays.
Biochemical Indicators of Hepatitis C Virus Infection
In chronic hepatitis C, increases in the alanine and aspartate aminotransferases range from zero to 20 times (but usually less than five times) the upper limit of normal.
Alanine aminotransferase (ALT) levels are usually higher than aspartate aminotransferase (AST) levels, but that finding may be reversed in patients who have cirrhosis.
Alkaline phosphatase and gamma glutamyl transpeptidase are usually normal. If elevated, they may indicate cirrhosis.
Low platelet and white blood cell counts and raised levels of serum globulins (including immunoglobulins and rheumatoid factor) are frequent in patients with severe fibrosis or cirrhosis, providing clues to the presence of advanced disease.
The enzymes lactate dehydrogenase and creatine kinase are usually normal.
Albumin levels, bilirubin, and prothrombin time are normal until late-stage disease.
Iron and ferritin levels may be slightly elevated.
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 (105) and 10,000,000 (107) copies per mL. Expressed as 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 and ribavirin are higher in patients with low levels of HCV RNA. There are several definitions of a “low level” of HCV RNA, but the usual definition is below 800,000 IU (~ 2 million copies) per mL.In addition, monitoring HCV RNA levels during the early phases of treatment may provide early 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
There are six known genotypes and more than 50 subtypes of hepatitis C. The genotype is helpful in defining the epidemiology of hepatitis C. More important, knowing the genotype or serotype (genotype-specific antibodies) of HCV is helpful in making recommendations and counseling regarding therapy. 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 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. 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.
Normal Serum ALT Levels
Up to 40 percent of patients with chronic hepatitis C have normal serum alanine aminotransferase (ALT) levels, even when tested on multiple occasions. In this and other situations in which the diagnosis of chronic hepatitis C may be questioned, the diagnosis should be confirmed by testing for HCV RNA. The presence of HCV RNA indicates that the patient has ongoing viral infection despite normal ALT levels.
Liver biopsy is not necessary for diagnosis but is helpful for grading the severity of disease and staging the degree of fibrosis and permanent architectural damage. Hematoxylin and eosin stains and Masson’s trichrome stain are used to grade the amount of necrosis and inflammation and to stage the degree of fibrosis. Specific immunohistochemical stains for HCV have not been developed for routine use. 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 the following changes in liver tissue:
Necrosis and inflammation at the edge of the portal areas, so-called “piecemeal necrosis” or “interface hepatitis”
Necrosis of hepatocytes and focal inflammation in the liver parenchyma
Inflammatory cells in the portal areas (“portal inflammation”)
Fibrosis may exist in an early stage, being confined to the portal tracts, an intermediate stage consisting of expansion of the portal tracts and bridging between portal areas or to the central area, or a late stage of frank cirrhosis characterized by architectural disruption of the liver with fibrosis and regeneration. Several scales are used to stage fibrosis. 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.
By assigning scores for severity, grading and staging of hepatitis are helpful in managing patients with chronic hepatitis. The degree of inflammation and necrosis can be assessed as none, minimal, mild, moderate, or severe. The degree of fibrosis can be similarly assessed. Scoring systems are particularly helpful in clinical studies on chronic hepatitis.
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 and if it is not read by a knowledgeable expert. In addition, liver biopsy is an invasive procedure that is expensive and not without complications. At least 20 percent of patients have pain requiring medications after liver biopsy. 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. Obviously, noninvasive means of grading and staging liver disease would be very helpful.
ALT levels, particularly if tested over an extended period, are reasonably accurate reflections of disease activity. Thus, patients with repeatedly normal ALT levels usually have mild inflammation and liver cell injury on liver biopsy. Furthermore, patients who maintain ALT levels above five times the upper limit of normal usually have marked inflammatory activity. But for the majority of patients with mild to moderate ALT elevations, the actual level is not very predictive of liver biopsy findings.
More important is a means to stage liver disease and measure fibrosis short of liver biopsy. 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 (AST) that is higher than ALT (reversal of the ALT/AST ratio), a high gamma glutamyl transpeptidase or alkaline phosphatase, a decrease in platelet count (which is perhaps the earliest change), elevations in serum globulins, and, of course, abnormal bilirubin, albumin, or prothrombin time. Physical findings of a firm liver, or enlarged spleen or prominent spider angionata or palmar erythema, are also danger signals. While none of these findings are completely reliable, their presence should raise the suspicion of significant fibrosis and lead to evaluation for treatment sooner rather than later.
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.