The term chronic hepatitis means active, ongoing inflammation of the liver persisting for more than six months that is detectable by biochemical and histologic means. It does not imply an etiology. The biochemical hallmark of chronic hepatitis is an increased serum aminotransferase (AST and ALT) with minimal elevation of alkaline phosphatase. When the inflammation is severe and/or prolonged, hepatic dysfunction may become apparent with an increase in serum bilirubin and INR/prothrombin time, and a decrease in serum albumin. Typically, biochemical tests are used to identify and follow patients with chronic hepatitis, while liver biopsies serve to more precisely define the nature of the chronic hepatitis and provide useful information regarding the extent of damage and prognosis.

Histologically, chronic hepatitis is characterized by infiltration of the portal tracts by inflammatory cells. These cells are predominantly mononuclear cells including lymphocytes, monocytes and plasma cells. Chronic hepatitis is designated as mild when the infiltrate is confined to the portal triad (Figure 9). It is designated as moderately severe chronic hepatitis (Figure 10) when the infiltrate extends into the parenchyma (piecemeal necrosis) and when it extends to adjacent portal triads (bridging). The inflammatory process can also "bridge" from the portal tract to the central vein. Severe chronic hepatitis is associated with multilobular or confluent necrosis and is much more likely to progress to cirrhosis. The amount of fibrosis is staged separately. These newer terms, mild, moderate and severe chronic hepatitis, replace the older terminology including chronic persistent hepatitis and chronic active hepatitis, which are still frequently mentioned in older textbooks.

By far, the commonest cause of chronic hepatitis is viral infections of the liver. Other causes include autoimmune hepatitis, drug-induced hepatitis, Wilson's disease, a₁-antitrypsin deficiency and steatohepatitis. Primary biliary cirrhosis and primary sclerosing cholangitis may occasionally mimic chronic hepatitis, but are not usually classified as such. An approach to help determine the etiology of chronic hepatitis is summarized in Table 7.

5.1.1 GENERAL CONSIDERATIONS

Of the known viral infections of the liver, HBV, HCV, HDV and HGV can cause chronic liver disease; HBV and HCV make up the vast majority of these cases. A careful history is most helpful in determining the cause of chronic hepatitis (Table 7). In most cases, selected laboratory tests will provide the confirmation of diagnosis. Sometimes liver biopsy is required to identify the cause of chronic hepatitis. The liver biopsy will also provide important information about the extent of damage and current activity.

5.1.2 HEPATITIS B VIRUS

5.1.2.1 Evolution to chronic liver disease

A number of factors determine whether an individual will clear an acute HBV infection or progress to a chronic carrier state. Of these, the age at infection is most important, with carrier rates of greater than 90% occurring in vertically infected newborns as compared to less than 5% in adults. The immunologic status of the host is also important, with immunocompromised individuals (e.g., HIV, renal failure, post-transplant) being more likely to become chronic carriers. The severity of the acute disease has also been correlated with outcome. In general, the milder the acute illness the more likely that progression to chronic liver disease will occur. Presumably, individuals with mild acute disease are those with a suboptimal immunologic response to the virus, whereas patients with more severe acute disease are manifesting a prompt and effective immunologic attack on hepatocytes harboring HBV.

5.1.2.2 Presentation

The majority of patients with chronic type B hepatitis are asymptomatic or have mild fatigue only. The patients might give a history of risk-taking behavior or a family history of hepatitis B infection. Liver enzyme abnormalities discovered incidentally frequently alert the physician to the possibility of underlying viral infection. Screening of family and sexual contacts of known cases will often discover additional cases.

5.1.2.3 Diagnosis

By the strictest definition, a patient is not a chronic HBV carrier until the HB_sAg test is found to be positive for six months, but the diagnosis is often suspected much earlier.

It is important not to be confused by other viral markers of previous hepatitis B exposure (Table 4). Antibodies to HB_sAg (anti-HBs) indicate immunity against HBV and may be acquired either after vaccination or after clearance of HBV infection. On the other hand, the presence of HB_eAg and HBV-DNA indicates active HBV replication. The level of HBV-DNA correlates with the amount of virus present in the circulation. When HBV-DNA is strongly positive, there is a high viral load, which indicates a high degree of infectivity (all physiologic fluids are potentially infectious). A negative HBV-DNA indicates very low or absent infectivity. Unfortunately, serum HBV-DNA testing is not widely available. If HB_eAg is negative there is usually lower infectivity. Positive antibodies to the core antigen (anti-HB_c) indicate exposure to the virus only and are therefore of very limited use in patient assessment. The presence of IgM and anti-HB_c suggests recent HBV exposure. In chronic HBV infection the anti-HBc is is positive but the IgM anti-HB_c is negative because exposure took place more than six months previously. The exception is in patients with reactivation of chronic hepatitis B who may also be IgM anti-HB_c positive, which reduces the usefulness of this test in the diagnosis of acute HBV infection.

5.1.2.4 Natural history

The natural history of chronic HBV infection has been well defined. The first six months of the illness represent the acute hepatitis phase of the infection. This acute phase is not often seen in chronically infected patients who have contracted the virus at birth or in early childhood. Chronic hepatitis has three phases, termed the replicative, inflammatory and inactive phases (Figure 11). During the replicative phase, HB_eAg is positive as is HBV-DNA, indicating high levels of viral replication. Despite this, the aminotransferases are normal or near normal and the liver biopsy is relatively inactive. For unknown reasons, patients may then enter the inflammatory phase in which their immune system now recognizes those hepatocytes harboring virus and begins to attack them. Accordingly, the aminotransferase becomes elevated and the biopsy shows chronic hepatitis, often of a severe degree The level of viral replication as measured by the HBV-DNA will decline. If the patient has successfully cleared viral replication, he or she will enter an inactive phase characterized by normalization of the aminotransferases and relative inactivity on the liver biopsy. HB_eAg will be cleared and anti-HB_e will form (seroconversion).

It is the severity and duration of the inflammatory phase that determine whether a patient will develop cirrhosis. This progression of chronic hepatitis to cirrhosis occurs in 20-30% of all chronic hepatitis B patients. Even patients who successfully enter the inactive phase are still at risk of hepatocellular carcinoma (relative risk greater than 100 vs the general population). Those with cirrhosis are at highest risk. Screening for hepatocellular carcinoma has been recommended in chronic carriers by performing a serum a-fetoprotein and an abdominal ultrasound each 6 to 12 months; more recently, however, the efficacy and cost benefit of this approach have been questioned. The problem is that even cases discovered by screening are often beyond cure by resection or liver transplantation.

5.1.2.5 Treatment

There are few therapeutic options for the treatment of patients with chronic hepatitis B, although different agents have been tried. Of these agents, only interferon-a has been licensed for use. In most studies, 30-40% of chronic hepatitis B patients successfully respond to interferon treatment with a loss of serologic markers of viral replication (HB_eAg and HBV-DNA). A minority of responders will also lose all evidence of infection (clear HB_sAg) during treatment, but up to 50% will become HB_sAg negative during the first five years of follow-up. The relapse rate following discontinuation of therapy is less than 15%.

Since the majority of patients do not respond to interferon, an important question is, which patients warrant a trial of therapy? Those most likely to respond include patients who acquired their infection during adulthood, females, patients with elevated ALT and low HBV-DNA levels, those with active hepatic inflammation on biopsy, patients who are HIV antibody negative and those who are anti-HDV negative. Stated another way, patients in the inflammatory phase (Figure 11) are most likely to benefit from interferon.

A number of new medications are being tested for efficacy against HBV. Lamivudine is a new nucleoside analogue with very potent antiviral effect against HBV. Its role in treatment of chronic hepatitis B is currently being defined in clinical trials; but it may find a use in combination with interferon.

5.1.2.6 Prevention

Active immunization is important to prevent transmission of HBV infection from a chronic carrier to sexual and family contacts. The safety of the vaccine is well established. It should be given to all high-risk groups as a minimum, but ultimately the goal is universal vaccination. As universal vaccination becomes a reality, prophylaxis with hyperimmune hepatitis B globulins for HBV contacts will become unnecessary.

5.1.3 HEPATITIS C VIRUS

Chronic hepatitis C virus has become the commonest type of chronic viral hepatitis in most areas. The identified cases may represent only the tip of the iceberg, with most cases still undiagnosed. Many cases are identified after investigation of raised liver enzymes in asymptomatic individuals or by the Red Cross during screening of blood donors. Other patients present to physicians with fatigue, malaise and abnormal liver enzymes.

5.1.3.1 Epidemiology

Although HCV infection can be transmitted by the same routes as HBV infection, the majority of cases are related to intravenous drug abuse (60-70%). Ten percent of patients with chronic HCV infection will have had a previous blood transfusion. In the remaining patients, one cannot identify a possible source of infection. Nonparenteral transmission through sexual or intimate contact and maternal-infant exposure can occur with HCV infection, but much less often than with HBV infection.

5.1.3.2 Natural history

The natural history of HCV infection has been better defined with the availability of anti-HCV serologic testing. Widespread application of this test has revealed that more than 75% of patients with acute HCV infection will remain chronically infected. Of the patients with chronic hepatitis, 20% either have or will go on to develop cirrhosis by 20 years. Thereafter, an additional 1% per year develop cirrhosis. Of much concern is the fact that recent data document a strong association between chronic HCV infection and hepatocellular carcinoma. The exact relative risk has yet to be determined but appears to be as high as or higher than that with HBV. Other disorders that have been described in association with chronic HCV infection include cryoglobulinemia, porphyria cutanea tarda and membranoproliferative glomerulonephritis.

5.1.3.3 Treatment

Interferon-a is the only therapy available for chronic HCV infection. Numerous studies have identified a 40-50% response rate (normalization of ALT abnormalities). However, at least 50% of these responders will relapse, with the majority of relapses occurring within three months following discontinuation of therapy. Therefore, only about 10-20% of treated patients enjoy a sustained response (presumed cure). The most recent clinical trials have utilized 12 to 24 months of therapy instead of the standard 6 months. Sustained response rates in excess of 30% have been published; however, longer therapy is associated with increased cost and more side effects. There are no strict guidelines for who should receive interferon treatment for chronic HCV infection. Factors that predict a favorable response to interferon include recent infection, minimally elevated ALT, absence of cirrhosis, low titer of virus in serum and certain hepatitis C genotypes (genetic variants).

A vaccine for HCV has not been developed, but is an active area of research. There are currently insufficient data to advocate the use of immune serum globulin for the prevention of HCV infection. Condoms should be used during the acute phase of the illness and indefinitely for patients who are immunocompromised. Couples in whom one is chronically infected with hepatitis C must make their own decision in regard to condom use after being advised of the risks; the risk of spread to regular sexual partners is 2-5%. Vertical transmission from a normal mother to her newborn is rare; however, the risk of HCV vertical transmission is much higher if the mother is co-infected by HIV.

5.1.4 HEPATITIS D VIRUS

Chronic hepatitis D usually results from HDV superinfection of an HBV carrier. Less commonly, acute HBV/HDV co-infection leads to chronic infection. Either way, chronic hepatitis D is usually aggressive and severe with rapid progression to cirrhosis.

The diagnosis is made by testing for anti-HDV in the serum of HBV carriers with risk factors for HDV infection. HDV antigen and HDV-RNA in serum or liver can also be measured, but only in a limited number of laboratories. In North America this virus is most often transmitted by intravenous drug abuse. In Mediterranean countries nonparenteral transmission may also occur. Treatment with interferon for HDV infection has been disappointing. Because of the dependency of HDV on HBV, prevention of HBV infection with vaccine can decrease HDV infection also.

Many drugs can cause chronic hepatitis. Whether to discontinue an implicated drug depends to some extent on whether the drug is merely causing persistent enzyme abnormalities or hepatic dysfunction with severe histologic abnormalities. In severe cases, fibrosis, cirrhosis and death from liver failure or complications of portal hypertension can result. Examples of drugs that are capable of causing chronic hepatitis that may progress to liver failure and portal hypertension are oxyphenisatin, isoniazid, nitrofurantoin, alpha methyldopa and dantrolene. On the other hand, if a drug is essential to the health of the patient and there are no unrelated agents that can be substituted, it is reasonable to continue therapy under close clinical supervision providing the enzyme abnormalities are mild and not associated with symptoms or functional derangements (i.e., serum bilirubin, albumin and INR/PT remain normal). Liver biopsy may be helpful in defining the severity of liver injury.

Autoimmune hepatitis is an immunologically mediated disorder of the liver that often affects young females with a personal or family history of autoimmune disease. The etiology is unknown. The onset may be insidious or acute. The hepatic presentation can be that of sudden hepatic failure, chronic hepatitis or inactive cirrhosis. The most common complaints include fatigue, amenorrhea, complaints associated with an accompanying rheumatological disorder such as arthritis, or those associated with thyroid disease. Physical findings include jaundice (in severe cases), spider nevi, palmar erythema and hepatosplenomegaly. Laboratory investigations reveal hypergammaglo-bulinemia with pronounced elevation of IgG levels, reduced serum albumin, positive antinuclear factor and smooth-muscle antibody. A proposed subclassification includes type 1 and type 2 autoimmune hepatitis, with the latter demonstrating antibodies to liver/kidney microsome (anti-LKM 1 hepatitis). Liver biopsy is essential to establish the diagnosis and severity of the underlying disease as well as to exclude other liver disease. Cirrhosis is present in over 50% of autoimmune hepatitis on initial biopsy.

Treatment is initiated with high-dose corticosteroids (prednisone 40-60 mg/day) for 4-6 weeks. The dose is then tapered to a maintenance level (e.g., 5-10 mg/day) just sufficient to keep the liver enzymes within normal values. Often azathioprine is used for its steroid-sparing effect. Following discontinuation of treatment, most patients will relapse, requiring reinitiation of therapy. Untreated autoimmune hepatitis progresses rapidly to cirrhosis (three to five years). Although corticosteroids may not prevent cirrhosis, they are clearly lifesaving in this otherwise fatal condition. With careful titration of their medication, most patients remain in stable condition for years. In the remaining minority, liver transplantation is highly successful.

This condition is usually readily diagnosed on clinical grounds (see Section 6). These features are contrasted with those of viral hepatitis in Table 8.

Nonalcoholic hepatosteatonecrosis (fatty liver) is a common disorder, usually asymptomatic, found most commonly in patients who are obese, diabetic and, occasionally, hyperlipidemic. Mild right upper quadrant pain may be present with aminotransferase levels typically <3-4 times normal. The diagnosis can be established by ultrasound (or CT) examination of the liver or by liver biopsy showing macrovesicular fat. The treatment is that of the underlying condition, including weight loss and therapy of diabetes and hyperlipidemia. Most cases of fatty liver are not associated with inflammation and hepatocellular necrosis. However, 10-20% have nonalcoholoic steatohepatitis and have the potential to progress on to fibrosis and cirrhosis.