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Chronic Hepatitis

by Anna E. Rutherford, MD, MPH

Chronic hepatitis is hepatitis that lasts > 6 mo. Common causes include hepatitis B and C viruses, autoimmune mechanisms (autoimmune hepatitis), and drugs. Many patients have no history of acute hepatitis, and the first indication is discovery of asymptomatic aminotransferase elevations. Some patients present with cirrhosis or its complications (eg, portal hypertension). Biopsy is necessary to confirm the diagnosis and to grade and stage the disease. Treatment is directed toward complications and the underlying condition (eg, corticosteroids for autoimmune hepatitis, antiviral therapy for viral hepatitis). Liver transplantation is often indicated for end-stage disease.

(See also the American Association for the Study of Liver Disease’s Diagnosis, Management, and Treatment of Hepatitis C .)

Etiology

Hepatitis lasting > 6 mo is generally defined as chronic, although this duration is arbitrary. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are frequent causes of chronic hepatitis; 5 to 10% of cases of HBV infection, with or without hepatitis D virus (HDV) coinfection, and about 75% of cases of HCV infection become chronic. Rates are higher for HBV infection in children (eg, up to 90% of infected neonates and 30 to 50% of young children). Hepatitis A and E viruses are not causes. Although the mechanism of chronicity is uncertain, liver injury is mostly determined by the patient’s immune reaction to the infection.

Many cases are idiopathic. A high proportion of idiopathic cases have prominent features of immune-mediated hepatocellular injury (autoimmune hepatitis), including the following:

  • The presence of serologic immune markers

  • An association with histocompatibility haplotypes common in autoimmune disorders (eg, HLA-B1, HLA-B8, HLA-DR3, HLA-DR4)

  • A predominance of T lymphocytes and plasma cells in liver histologic lesions

  • Complex in vitro defects in cellular immunity and immunoregulatory functions

  • An association with other autoimmune disorders (eg, RA, autoimmune hemolytic anemia, proliferative glomerulonephritis)

  • A response to therapy with corticosteroids or immunosuppressants

Sometimes chronic hepatitis has features of both autoimmune hepatitis and another chronic liver disorder (eg, primary biliary cirrhosis, chronic viral hepatitis). These conditions are called overlap syndromes.

Many drugs, including isoniazid, methyldopa, nitrofurantoin, and, rarely acetaminophen, can cause chronic hepatitis. The mechanism varies with the drug and may involve altered immune responses, cytotoxic intermediate metabolites, or genetically determined metabolic defects.

Other causes of chronic hepatitis include alcoholic hepatitis and nonalcoholic steatohepatitis. Less often, chronic hepatitis results from α 1 -antitrypsin deficiency, celiac disease, a thyroid disorder, or Wilson disease.

Cases were once classified histologically as chronic persistent, chronic lobular, or chronic active hepatitis. A more useful recent classification system specifies the etiology, the intensity of histologic inflammation and necrosis (grade), and the degree of histologic fibrosis (stage). Inflammation and necrosis are potentially reversible; fibrosis usually is not.

Symptoms and Signs

Clinical features vary widely. About one third of cases develop after acute hepatitis, but most develop insidiously de novo. Many patients are asymptomatic, especially in chronic HCV infection. However, malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nonspecific upper abdominal discomfort. Jaundice is usually absent. Often, particularly with HCV, the first findings are signs of chronic liver disease (eg, splenomegaly, spider nevi, palmar erythema) or complications of cirrhosis (eg, portal hypertension, ascites, encephalopathy). A few patients with chronic hepatitis develop manifestations of cholestasis (eg, jaundice, pruritus, pale stools, steatorrhea). In autoimmune hepatitis, especially in young women, manifestations may involve virtually any body system and can include acne, amenorrhea, arthralgia, ulcerative colitis, pulmonary fibrosis, thyroiditis, nephritis, and hemolytic anemia.

Chronic HCV is occasionally associated with lichen planus, mucocutaneous vasculitis, glomerulonephritis, porphyria cutanea tarda, and, perhaps, non-Hodgkin B-cell lymphoma. About 1% of patients develop symptomatic cryoglobulinemia with fatigue, myalgias, arthralgias, neuropathy, glomerulonephritis, and rashes (urticaria, purpura, or leukocytoclastic vasculitis); asymptomatic cryoglobulinemia is more common.

Diagnosis

  • Liver function test results compatible with hepatitis

  • Viral serologic tests

  • Possibly autoantibodies, immunoglobulins, α 1 -antitrypsin level, and other tests

  • Usually biopsy

  • Serum albumin, platelet count, and PT

(See also the American Association for the Study of Liver Disease’s practice guideline Diagnosis, Management, and Treatment of Hepatitis C and the U.S. Preventive Services Task Force’s clinical guideline Screening for Hepatitis C in Adults .)

The diagnosis is suspected in patients with suggestive symptoms and signs, incidentally noted elevations in aminotransferase levels, or previously diagnosed acute hepatitis. In addition, to identify asymptomatic patients, the CDC recommends testing all people born between 1945 and 1965 once for hepatitis C. Liver function tests are needed if not previously done and include serum ALT, AST, alkaline phosphatase, and bilirubin. Aminotransferase elevations are the most characteristic laboratory abnormalities. Although levels can vary, they are typically 100 to 500 IU/L. ALT is usually higher than AST. Aminotransferase levels can be normal during chronic hepatitis if the disease is quiescent, particularly with HCV. Alkaline phosphatase is usually normal or only slightly elevated but is occasionally markedly high. Bilirubin is usually normal unless the disease is severe or advanced. However, abnormalities in these laboratory tests are not specific and can result from other disorders, such as alcoholic liver disease, recrudescent acute viral hepatitis, and primary biliary cirrhosis.

If laboratory results are compatible with hepatitis, viral serologic tests are done to exclude HBV and HCV (see Table: and ). Unless these tests indicate viral etiology, further testing is required. The first tests done include autoantibodies, immunoglobulins, thyroid tests (thyroid-stimulating hormone), tests for celiac disease (tissue transglutaminase antibody), and α 1 -antitrypsin level. Children and young adults are screened for Wilson disease by measuring the ceruloplasmin level. Marked elevations in serum immunoglobulins suggest chronic autoimmune hepatitis but are not conclusive. Autoimmune hepatitis is normally diagnosed based on the presence of antinuclear (ANA), anti–smooth muscle, or anti-liver/kidney microsomal type 1 (anti-LKM1) antibodies at titers of 1:80 (in adults) or 1:20 (in children). (See also the American Association for the Study of Liver Disease's practice guideline Diagnosis and Management of Autoimmune Hepatitis .)

Unlike in acute hepatitis, biopsy is necessary. Mild cases may have only minor hepatocellular necrosis and inflammatory cell infiltration, usually in portal regions, with normal acinar architecture and little or no fibrosis. Such cases rarely develop into clinically important liver disease or cirrhosis. In more severe cases, biopsy typically shows periportal necrosis with mononuclear cell infiltrates (piecemeal necrosis) accompanied by variable periportal fibrosis and bile duct proliferation. The acinar architecture may be distorted by zones of collapse and fibrosis, and frank cirrhosis sometimes coexists with signs of ongoing hepatitis. Biopsy is also used to grade and stage the disease.

In most cases, the specific cause of chronic hepatitis cannot be discerned via biopsy alone, although cases caused by HBV can be distinguished by the presence of ground-glass hepatocytes and special stains for HBV components. Autoimmune cases usually have a more pronounced infiltration by lymphocytes and plasma cells. In patients with histologic but not serologic criteria for chronic autoimmune hepatitis, variant autoimmune hepatitis is diagnosed; many have overlap syndromes.

Serum albumin, platelet count, and PT should be measured to determine severity; low serum albumin, a low platelet count, or prolonged PT may suggest cirrhosis and even portal hypertension.

If symptoms or signs of cryoglobulinemia develop during chronic hepatitis, particularly with HCV, cryoglobulin levels and rheumatoid factor should be measured; high levels of rheumatoid factor and low levels of complement suggest cryoglobulinemia.

Patients with chronic HBV infection should be screened every 6 to 12 mo for hepatocellular cancer with ultrasonography and serum α-fetoprotein measurement, although the cost-effectiveness of this practice is debated. (See also the Cochrane review abstract on alpha-fetoprotein and/or liver ultrasonography for liver cancer screening in patients with chronic hepatitis B .) Patients with chronic HCV infection should be similarly screened only if advanced fibrosis or cirrhosis is present.

Prognosis

Prognosis is highly variable. Chronic hepatitis caused by a drug often regresses completely when the causative drug is withdrawn. Without treatment, cases caused by HBV can resolve (uncommon), progress rapidly, or progress slowly to cirrhosis over decades. Resolution often begins with a transient increase in disease severity and results in seroconversion from hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe). Coinfection with HDV causes the most severe form of chronic HBV infection; without treatment, cirrhosis develops in up to 70% of patients. Untreated chronic hepatitis due to HCV causes cirrhosis in 20 to 30% of patients, although development may take decades. Chronic autoimmune hepatitis usually responds to therapy but sometimes causes progressive fibrosis and eventual cirrhosis.

Chronic HBV infection increases the risk of hepatocellular cancer. The risk is also increased in chronic HCV infection, but only if cirrhosis has already developed (see Hepatocellular Carcinoma).

Treatment

  • Supportive care

  • Treatment of cause (eg, corticosteroids for autoimmune hepatitis, antivirals for HBV and HCV infection)

Treatment goals include treating the cause and managing complications (eg, ascites, encephalopathy). Drugs that cause hepatitis should be stopped. Underlying disorders, such as Wilson disease, should be treated. In chronic hepatitis due to HBV, prophylaxis (including immunoprophylaxis) for contacts of patients may be helpful (see Acute Viral Hepatitis : Prevention). No vaccination is available for contacts of patients with HCV infection.

Corticosteroids and immunosuppressants should be avoided in chronic hepatitis B and C because these drugs enhance viral replication. If patients with chronic hepatitis B require treatment with corticosteroids, immunosuppressive therapies, or cytotoxic chemotherapy for other disorders, they should be treated with antiviral drugs at the same time to prevent a flare-up of acute hepatitis B or acute liver failure due to hepatitis B.

Autoimmune hepatitis

(See also the American Association for the Study of Liver Disease’s practice guideline Diagnosis and Management of Autoimmune Hepatitis .) Corticosteroids, with or without azathioprine, prolong survival. Prednisone is usually started at 30 to 60 mg po once/day, then tapered to the lowest dose that maintains aminotransferases at normal or near-normal levels. Some experts give concomitant azathioprine 1 to 1.5 mg/kg po once/day; others add azathioprine only if low-dose prednisone fails to maintain suppression. Most patients require long-term, low-dose maintenance treatment. Liver transplantation may be required for end-stage disease.

HBV

(See also the American Association for the Study of Liver Disease’s practice guideline update on chronic hepatitis B.) Antiviral treatment is indicated for patients with elevated aminotransferase levels, clinical or biopsy evidence of progressive disease, or both. The goal is to eliminate HBV-DNA. Treatment may need to be continued indefinitely and thus may be very expensive; stopping treatment prematurely can lead to relapse, which may be severe. However, treatment may be stopped if HBeAg converts to anti-HBe or if tests for hepatitis B surface antigen (HBsAg) become negative. Drug resistance is also a concern. Seven antiviral drugs—entecavir, adefovir, lamivudine, interferon alfa (INF-α), pegylated INF-α (peginterferon-α), telbivudine, and tenofovir—are available (see Table: Comparison of Drugs Commonly Used to Treat Chronic Viral Hepatitis B).

Comparison of Drugs Commonly Used to Treat Chronic Viral Hepatitis B

INF-α

PEG IFN-α

Lamivudine

Adefovir

Entecavir

Telbivudine

Tenofovir

Effect

Percentage of Patients

Serum HBV-DNA becomes undetectable

37%

25%

44%

21%

67%

60%

76%

Seroconversion from HBeAg to anti-Hbe occurs

18%

27%

16–21%

12%

21%

22%

21%

ALT normalizes

23%

39%

41–75%

48%

68%

77%

68%

Histologic improvement occurs

NA

38%

49–56%

53%

72%

65%

74%

HBsAg becomes undetectable (at 1 yr)*

8%

3%

< 1%

0%

2%

0%

3%

Resistance develops

None

None

At 1 yr: ~14–32%

At 5 yr: ~60–70%

At 1 yr: 0%

At 5 yr: 29%

At 1 yr: 0%

At 5 yr: 1.2%

At 1 yr: 5%

At 2 yr: 25%

At 3 yr: 0%

After 3 yr: Unknown

anti-Hbe = antibody to HBeAg; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; INF-α = interferon alfa; PEG IFN-α = pegylated INF-α.

Adapted from Lok ASF, McMahon BJ: Chronic hepatitis B: Update 2009. American Association for the Study of Liver Diseases (AASLD) practice guidelines update. Hepatology 50: 661–699, 2009.

First-line treatment is usually with an oral antiviral drug, such as entecavir (a nucleoside analog) or tenofovir (a nucleotide analog). Oral antiviral drugs have few adverse effects and can be given to patients with decompensated liver disease. Combination therapy has not proved superior to monotherapy, but studies continue to examine their comparative usefulness. HBsAg becomes undetectable and HBeAg seroconversion occurs in patients with HBeAg-positive chronic HBV infection; these patients may be able to stop antiviral drugs. Patients with HBeAg-negative chronic HBV infection almost always need to take antiviral drugs indefinitely to maintain viral suppression; they have already developed antibodies to HBeAg, and thus the only specific criterion for stopping HBV treatment would be HBsAg that becomes undetectable.

Entecavir has a high antiviral potency, and resistance to it is uncommon; it is considered a first-line treatment for HBV infection. Entecavir is effective against adefovir-resistant strains. Dosage is 0.5 mg po once/day; however, patients who have previously taken a nucleoside analog should take 1 mg po once/day. Dose reduction is required in patients with renal insufficiency. Serious adverse effects appear to be uncommon, although safety in pregnancy has not been established.

Tenofovir has replaced adefovir (an older nucleotide analog) as a first-line treatment. Tenofovir is the most potent oral antiviral for hepatitis B; resistance to it is minimal. It has few adverse effects. Dosage is 300 mg po once/day; dosing frequency may need to be reduced if creatinine clearance is reduced.

For adefovir , dosage is 10 mg po once/day.

Interferon alfa (IFN- α ) can be used but is no longer considered first-line treatment. Dosage is 5 million IU sc once/day or 10 million IU sc 3 times/wk for 16 to 24 wk in patients with HBeAg-positive chronic HBV infection and for 12 to 24 mo in patients with HBeAg-negative chronic HBV infection. In about 40% of patients, this regimen eliminates HBV-DNA and causes seroconversion to anti-HBe; a successful response is usually presaged by a temporary increase in aminotransferase levels. The drug must be given by injection and is often poorly tolerated. The first 1 or 2 doses cause an influenza-like syndrome. Later, fatigue, malaise, depression, bone marrow suppression, and, rarely, bacterial infections or autoimmune disorders can occur. In patients with advanced cirrhosis, IFN-α can precipitate liver failure and is therefore contraindicated. Other contraindications include renal failure, immunosuppression, solid organ transplantation, and cytopenia. In a few patients, treatment must be stopped because of intolerable adverse effects. The drug should be given cautiously or not at all to patients with ongoing substance abuse or a major psychiatric disorder. Pegylated IFN-α can be used instead of IFN-α. Dosage is usually 180 mcg by injection once/wk for 48 wk. Adverse effects are similar to those of IFN-α but may be less severe.

Lamivudine (a nucleoside analog) is no longer considered first-line treatment for HBV infection because risk of resistance is higher and efficacy is lower than those of newer antiviral drugs. Dosage is 100 mg po once/day; it has few adverse effects.

Telbivudine is a newer nucleoside analog that has greater efficacy and potency than lamivudine but also has a high rate of resistance; it is not considered first-line treatment. Dosage is 600 mg po once/day.

Liver transplantation should be considered for end-stage liver disease caused by HBV. In patients with HBV infection, the long-term use of first-line oral antivirals and peritransplantation use of hepatitis B immune globulin (HBIG) has improved outcomes after liver transplantation. Survival is equal to or better than that after transplantation for other indications, and recurrences of hepatitis B are minimized.

HCV

(See also the American Association for the Study of Liver Disease’s practice guidelines Diagnosis, Management, and Treatment of Hepatitis C and Treatment of Genotype 1 Chronic HCV Virus Infection and Long-Term Management of the Successful Adult Liver Transplant .) For chronic hepatitis due to HCV, treatment is indicated if aminotransferase levels are elevated and biopsy shows active inflammatory disease with evolving fibrosis. The goal of treatment is permanent elimination of HCV-RNA (sustained virologic response), which is associated with permanent normalization of aminotransferase and cessation of histologic progression. Treatment results are more favorable in patients with moderate fibrosis and a viral load of < 600,000 to 800,000 IU/mL than in patients with cirrhosis and a viral load of > 800,000 IU/mL.

HCV genotype is determined before treatment because genotype influences the course, duration, and success of treatment. Genotype 1 is more common than genotypes 2, 3, 4, 5, and 6; it accounts for 70 to 80% of cases of chronic hepatitis C in the US.

Traditionally, patients with all genotypes are treated with pegylated IFN-α plus ribavirin (dual therapy—see below). Patients with genotype 1 are also given a protease inhibitor (telaprevir, boceprevir, simeprevir).

Many direct-acting antivirals are being developed. These drugs affect specific HCV targets, such as proteases or polymerases. The polymerase inhibitor sofosbuvir is effective against HCV genotypes 1 to 6 and can be used without interferon, providing an all-oral regimen of sofosbuvir plus ribavirin for genotypes 2 and 3. This regimen is particularly useful for patients who are infected with HCV genotypes 2 or 3 (and are thus not eligible for treatment with protease inhibitors) or who have contraindications to or have not responded to treatment with interferon-based regimens.

Decompensated cirrhosis due to hepatitis C is the most common indication for liver transplantation in the US. HCV recurs almost universally in the graft, and both patient and graft survival are less favorable than when transplantation is done for other indications. Several direct-acting antivirals and interferon-free regimens are being studied in patients who have hepatitis C and have received a liver transplant.

HCV genotype 1

Genotype 1 is more resistant to treatment with dual therapy with pegylated IFN-α plus ribavirin than other genotypes. Adding a protease inhibitor (telaprevir, boceprevir, or simeprevir) or polymerase inhibitor (sofosbuvir) to pegylated IFN-α plus ribavirin increases the rate of sustained virologic response from < 50% (with dual therapy) to 70 to 90%.

Pegylated IFN- α 2b 1.5 mcg/kg sc once/wk and pegylated IFN- α 2a 180 mcg sc once/wk have comparable results. Adverse effects of pegylated IFN-α are similar to those of IFN-α but may be less severe; contraindications are also similar (see above).

For ribavirin , dosage is 500 to 600 mg po bid. Ribavirin is usually well-tolerated but commonly causes anemia due to hemolysis; dosage should be decreased if hemoglobin decreases to < 10 g/dL. Ribavirin is teratogenic in both men and women, requiring contraception during treatment and for 6 mo after treatment is completed. Patients who cannot tolerate ribavirin should still be given pegylated IFN-α, but not using ribavirin reduces the likelihood of successful treatment. Ribavirin monotherapy is of no value.

If telaprevir is the protease inhibitor chosen, it is given at a dose of 750 mg po tid for 12 wk. The HCV-RNA level should be measured 4 and 12 wk after beginning treatment. If HCV-RNA is undetectable at 4 and 12 wk, triple therapy is followed by another 12 wk of dual therapy with pegylated IFN-α and ribavirin (total treatment duration of 24 wk). However, dual therapy should be continued for 36 wk after triple therapy (total treatment duration of 48 wk) if patients have the following:

  • No response to previous antiviral therapies (HCV-RNA did not decrease by at least 2 log levels after treatment for 12 wk) or an incomplete response (called partial responders)

  • HCV-RNA that is detectable at 4 or 12 wk after beginning triple therapy

  • Compensated cirrhosis

If boceprevir is chosen, it is always given at a dose of 800 mg po tid, beginning 4 wk after starting dual therapy with pegylated IFN-α plus ribavirin. The HCV-RNA level should be measured at 4, 8, 12, and 24 wk after beginning treatment. If HCV-RNA is undetectable at 8 and 24 wk, triple therapy is given for 24 wk (total treatment duration of 28 wk). In certain cases, treatment duration is increased, as follows:

  • If patients responded only partially to previous antiviral therapy and have no detectable HCV-RNA at 8 or 24 wk: 32 wk of triple therapy (total treatment duration of 36 wk)

  • If patients have detectable HCV-RNA at 8 wk: 32 wk of triple therapy, followed by 12 wk of dual therapy (treatment duration of 48 wk)

  • If patients have detectable HCV-RNA at 4 wk and are tolerating triple therapy: 44 wk of triple therapy (total treatment duration of 48 wk)

  • If patients have not responded to previous antiviral therapy or have compensated cirrhosis: 44 wk of triple therapy (total treatment duration of 48 wk)

If simeprevir , a 2nd-generation protease inhibitor, is chosen, it is given at a dose of 150 mg po once/day with pegylated IFN-α plus ribavirin for 12 wk; pegylated IFN-α plus ribavirin is then continued for another 12 wk (total treatment duration of 24 wk). In patients with HCV genotype 1a, pretreatment testing for a protease polymorphism (Q80K) is recommended because if it is present, simpeprevir is less likely to cause a sustained virologic response. The HCV-RNA level should be measured at 4, 12, and 24 wk. If HCV-RNA at 4 wk is undetectable or < 25 IU/mL, treatment should be continued for a total of 24 wk. If HCV-RNA measures > 25 IU/mL at 4 wk or any treatment week thereafter, treatment should be stopped because a sustained virologic response is unlikely to occur.

If sofosbuvir , a polymerase inhibitor, is chosen, it is given at a dose of 400 mg po once/day for 12 wk with pegylated IFN plus ribavirin.

Telaprevir, boceprevir, and simeprevir can cause anemia. Telaprevir can also cause rashes. All protease inhibitors can result in numerous drug-drug interactions.

HCV genotypes 2, 3, 4, 5, and 6

For genotype 2 , dual therapy with sofosbuvir 400 mg po once/day plus ribavirin 500 to 600 mg po bid for 12 wk is recommended.

For genotype 3 , dual therapy with sofosbuvir plus ribavirin 500 to 600 mg po bid for 24 wk is recommended.

For genotype 4, 5, and 6 , sofosbuvir 400 mg po once/day plus pegylated IFN and ribavirin 500 to 600 mg po bid for 12 wk is recommended. An alternative regimen for genotype 4 is simeprevir 150 mg po once/day for 12 wk plus ribavirin 500 to 600 mg po bid and pegylated IFN for 24 to 48 wk. An alternative regimen for genotypes 5 and 6 is ribavirin 500 to 600 mg po bid and pegylated IFN-α for 48 wk.

HEV

Preliminary studies suggest antiviral efficacy for ribavirin in treatment of chronic hepatitis E.

Key Points

  • Chronic hepatitis is usually not preceded by acute hepatitis and is often asymptomatic.

  • If liver function test results (eg, unexplained elevations in aminotransferase levels) are compatible with chronic hepatitis, do serologic tests for hepatitis B and C.

  • If serologic results are negative, do tests (eg, autoantibodies, immunoglobulins, α 1 -antitrypsin level) for other forms of hepatitis.

  • Do a liver biopsy to confirm the diagnosis and assess the severity of chronic hepatitis.

  • Treat autoimmune hepatitis with corticosteroids and sometimes azathioprine.

  • Consider entecavir and tenofovir as first-line therapies for chronic hepatitis B.

  • Treat chronic hepatitis C with ribavirin and sofosbuvir plus pegylated INF (except in genotype 2 and 3); protease inhibitors telaprevir, boceprevir, and simeprevir can be used instead of sofosbuvir for genotype 1.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • FURADANTIN, MACROBID, MACRODANTIN
  • No brand name
  • LANIAZID
  • TYLENOL
  • IMURAN
  • RAYOS
  • VIREAD
  • BARACLUDE
  • EPIVIR
  • HEPSERA
  • TYZEKA
  • VIRAZOLE
  • VICTRELIS

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