Chronic hepatitis is hepatitis that lasts 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver disease (autoimmune hepatitis). 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 sometimes 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 decompensated cirrhosis.
(See also Causes of Hepatitis, Overview of Acute Viral Hepatitis, and Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Disease–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection.)
Hepatitis lasting > 6 months is generally defined as chronic, although this duration is arbitrary.
Etiology of Chronic Hepatitis
Common causes
The most common causes of chronic hepatitis are
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 developing chronic HBV infection in children (eg, up to 90% of infected neonates and 25 to 50% of young children). Although the mechanism of chronicity is uncertain, liver injury is mostly determined by the patient’s immune reaction to the infection.
Rarely, hepatitis E virus genotype 3 has been implicated in chronic hepatitis.
Hepatitis A virus does not cause chronic hepatitis.
NAFLD develops most often in patients with at least one of the following risk factors:
Obesity
Dyslipidemia
Insulin resistance
NASH is the progressive form of NAFLD that causes chronic hepatitis.
Alcohol-related liver disease (a combination of fatty liver, diffuse liver inflammation, and liver necrosis) results from excess alcohol consumption.
Less common causes
Autoimmune hepatitis (immune-mediated hepatocellular injury) accounts for a high proportion of hepatitis not caused by viruses or steatohepatitis; features of autoimmune hepatitis include the following:
The presence of serologic immune markers (eg, antinuclear antibodies, anti–smooth muscle antibodies, liver-kidney microsomal antibodies)
An association with histocompatibility haplotypes common in autoimmune disorders (eg, HLA-B1, HLA-B8, HLA-DR3, HLA-DR4)
A predominance of T cells and plasma cells in histologic liver lesions
Complex in vitro defects in cellular immunity and immunoregulatory functions
An association with other autoimmune disorders (eg, rheumatoid arthritis, autoimmune hemolytic anemia, proliferative glomerulonephritis)
A response to therapy with corticosteroids or immunosuppressants
Primary biliary cholangitis (formerly, primary biliary cirrhosis) is an immune-mediated process resulting in bile duct injury. Patients usually present with a positive antimitochondrial antibody (AMA) test and elevated alkaline phosphatase. Most patients with primary biliary cholangitis are women. Symptoms include fatigue, joint pain, and pruritus.
Sometimes chronic hepatitis has features of both autoimmune hepatitis and another immune-mediated chronic liver disorder (eg, primary biliary cholangitis, primary sclerosing cholangitis). These conditions are called overlap syndromes.
Many drugs
Less often, chronic hepatitis results from alpha-1 antitrypsin deficiency, celiac disease, a thyroid disorder, hereditary hemochromatosis, or Wilson disease.
Classification of Chronic Hepatitis
Cases of chronic hepatitis were once classified histologically as chronic persistent, chronic lobular, or chronic active hepatitis. Current classification specifies the following:
Etiology
Intensity of histologic inflammation and necrosis (grade)
Degree of histologic fibrosis (stage)
Inflammation and necrosis are potentially reversible. Fibrosis can be reversible if the cause is fully treated in patients who do not have cirrhosis.
Symptoms and Signs of Chronic Hepatitis
Clinical features of chronic hepatitis vary widely. About one third of cases develop after acute hepatitis, but most develop insidiously de novo.
Many patients are asymptomatic, regardless of the etiology. However, malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nonspecific upper abdominal discomfort. Jaundice is usually absent.
Often, the first findings are
Signs of cirrhosis (eg, splenomegaly, spider nevi, palmar erythema)
Complications of cirrhosis (eg, portal hypertension, variceal bleeding, ascites, encephalopathy, liver cancer)
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 hepatitis C is occasionally associated with lichen planus, mucocutaneous vasculitis, glomerulonephritis, porphyria cutanea tarda, mixed cryoglobulinemia, and, perhaps, non-Hodgkin B-cell lymphoma. Symptoms of cryoglobulinemia include fatigue, myalgias, arthralgias, neuropathy, glomerulonephritis, and rashes (urticaria, purpura, leukocytoclastic vasculitis); asymptomatic cryoglobulinemia is more common.
Diagnosis of Chronic Hepatitis
Liver test results compatible with hepatitis
Viral serologic tests
Possibly autoantibodies, immunoglobulins, alpha-1 antitrypsin level, and other tests
Occasionally biopsy
(See also the practice guideline Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Disease–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection and the U.S. Preventive Services Task Force’s clinical guideline Hepatitis C Virus Infection in Adolescents and Adults: Screening.)
Chronic hepatitis is suspected in patients with any of the following:
Suggestive symptoms and signs
Incidentally noted elevations in aminotransferase levels
Previously diagnosed acute hepatitis
In addition, to identify asymptomatic patients, the Centers for Disease Control (CDC) recommends testing of all adults ≥ 18 years at least once for hepatitis C.
Liver tests
Liver tests are needed if not previously done and include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin.
Aminotransferase elevations are the most characteristic laboratory abnormalities (ALT normal values: 29 to 33 IU/L [0.48 to 55 microkat/L] for males and 19 to 25 IU/L [0.32 to 0.42 microkat/L] for females [1]). ALT is usually higher than AST. Aminotransferase levels can be normal during chronic hepatitis if the disease is quiescent, particularly with HCV infection and nonalcoholic fatty liver disease (NAFLD).
Alkaline phosphatase is usually normal or only slightly elevated but is occasionally markedly high, particularly in primary biliary cholangitis.
Bilirubin is usually normal unless the disease is severe or advanced.
Other laboratory tests
If laboratory results are compatible with hepatitis, viral serologic tests are done to exclude HBV and HCV (see tables Hepatitis B Serology and Hepatitis C Serology). Unless these tests indicate viral etiology, further testing is required.
The next tests done include
Autoantibodies (antinuclear antibody, anti–smooth muscle antibody, antimitochondrial antibody, liver-kidney microsomal antibody)
Immunoglobulins
Serum transferrin saturation and ferritin
Thyroid tests (thyroid-stimulating hormone)
Tests for celiac disease (tissue transglutaminase antibody)
Alpha-1 antitrypsin level
Ceruloplasmin
Children and young adults are screened for Wilson disease by measuring the ceruloplasmin level.
Autoimmune hepatitis is normally diagnosed based on the presence of antinuclear (ANA), anti–smooth muscle (ASMA), or anti-liver/kidney microsomal type 1 (anti-LKM1) antibodies at titers of 1:80 (in adults) or 1:20 (in children) and usually elevations in serum immunoglobulins. Antimitochondrial antibodies most often present in primary biliary cholangitis. (See also the American Association for the Study of Liver Disease's practice guideline Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases.)
Serum transferrin saturation > 45% and elevated ferritin suggests hereditary hemochromatosis and should be followed by genetic testing for the hemochromatosis gene (HFE).
cirrhosis and even portal hypertension.
If the cause of hepatitis is identified, noninvasive tests (eg, ultrasound elastography, serum markers) can be done to assess the degree of liver fibrosis.
Biopsy
Unlike in acute hepatitis, biopsy may be necessary to confirm the diagnosis or etiology of chronic hepatitis.
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, although noninvasive testing (serum markers or elastrography) is now often used instead of liver biopsy to stage fibrosis. One of the simplest markers to stage fibrosis is the FIB4 index, which uses aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, and age to assess risk of advanced fibrosis. Other modalities include transient elastography or MR elastography
Screening for complications
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 or cirrhosis due to any underlying liver disorder should be screened every 6 months for hepatocellular carcinoma with ultrasonography and sometimes serum alpha-fetoprotein measurement, although the cost-effectiveness of this practice, particularly alpha-fetoprotein measurement, is debated. (See also the Cochrane review abstract Alpha-foetoprotein and/or liver ultrasonography for liver cancer screening in patients with chronic hepatitis B.)
Diagnosis reference
1. Kwo PY, Cohen SM, Lim JK: ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol 112 (1):18-35, 2017. doi: 10.1038/ajg.2016.517.
Prognosis for Chronic Hepatitis
Prognosis for patients with chronic hepatitis is highly variable and often depends on the cause and availability of treatment.
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) followed by the loss of hepatitis B surface antigen (HBsAg). Coinfection with HDV causes the most severe form of chronic HBV infection; without treatment, cirrhosis develops in up to 70% of patients with coinfection.
Untreated chronic hepatitis due to HCV causes cirrhosis in 20 to 30% of patients, although development may take decades and varies because it is often related to a patient's other risk factors for chronic liver disease, including alcohol use and obesity.
Chronic autoimmune hepatitis usually responds to therapy but sometimes causes progressive fibrosis and eventual cirrhosis.
Chronic HBV infection, even in the absence of cirrhosis, increases the risk of hepatocellular carcinoma. The risk is also increased in other liver disorders (eg, HCV infection, nonalcoholic fatty liver disease [NAFLD]), but usually when cirrhosis or advanced fibrosis has developed.
Treatment of Chronic Hepatitis
Supportive care
Treatment of cause (eg, corticosteroids for autoimmune hepatitis, antivirals for HBV and HCV infection)
General treatment
Treatment goals for chronic hepatitis include treating the cause and, if cirrhosis and portal hypertension have developed, managing complications (eg, ascites, encephalopathy).
Underlying disorders should be treated. Lifestyle changes should be recommended for patients with NAFLD or alcohol-related liver disease.
Liver transplantation may be required for decompensated cirrhosis.
Chronic hepatitis B and C
There are specific antiviral treatments for chronic hepatitis Bantiviral treatments for chronic hepatitis C (eg, interferon-free regimens of direct-acting antivirals).
In chronic hepatitis due to HBV, prophylaxis (including immunoprophylaxis) for contacts of patients may be helpful. 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 have other disorders that require treatment with corticosteroids, immunosuppressive therapies, or cytotoxic chemotherapy, they should be treated with antiviral drugs at the same time to prevent a flare or reactivation of hepatitis B or acute liver failure due to hepatitis B. A similar situation with hepatitis C being activated or causing acute liver failure has not been described.
Nonalcoholic steatohepatitis (NASH)
Treatment of NASH aims to
Reduce weight
Control risk factors and comorbidities
It may involve
Recommending weight loss of 7 to 10% of body weight via dietary changes and exercise
Avoiding exposure to toxins (eg, pesticides)
No pharmacotherapy is currently recommended specifically for the treatment of NASH
Autoimmune hepatitis
(See also the American Association for the Study of Liver Disease’s practice guideline Diagnosis and Management of Autoimmune Hepatitis.)
Corticosteroids,
Hereditary hemochromatosis
Hereditary hemochromatosis is treated with phlebotomy.
Key Points
Chronic hepatitis is usually not preceded by acute hepatitis and is often asymptomatic.
If liver 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, alpha-1 antitrypsin level) for other forms of hepatitis.
Consider a liver biopsy to confirm the diagnosis and assess the severity of chronic hepatitis if noninvasive testing is nondiagnostic.
Noninvasive tests (eg, elastography, serum markers) can be used to assess the degree of liver fibrosis.
Treat chronic hepatitis C of all genotypes with interferon-free regimens of direct-acting antivirals.
Encourage diet and exercise for weight loss (10% if possible) in patients with nonalcoholic fatty liver disease (NAFLD).
Treat hereditary hemochromatosis with phlebotomy.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
American Association for the Study of Liver Disease (AASLD) Practice Guidelines: A multidisciplinary panel of experts developed guidelines for diagnosing and managing various hepatic disorders using clinically relevant questions, which are answered by systematic reviews of the literature and followed by data-supported recommendations. The panel rated the quality (level) of the evidence and strength of each recommendation. Accessed July 6, 2022.
U.S. Preventive Services Task Force’s Hepatitis C Virus Infection in Adolescents and Adults: Screening: This web site summarizes the recommendations for hepatitis C screening and provides links to the full recommendations. It discusses assessment of risk and use of screening tests, including screening intervals. Accessed July 6, 2022.
AASLD Practice Guidelines: Diagnosis and Management of Autoimmune Hepatitis in Adults and children: This 2019 guideline addresses clinically relevant questions, using current evidence, expert opinion, systematic reviews of the literature, and the quality of evidence. This guideline updates the epidemiology, diagnosis, management, and outcomes of autoimmune hepatitis in adults and children from the 2010 guidelines. Accessed July 6, 2022.
Alpha-foetoprotein and/or Liver Ultrasonography for Liver Cancer Screening in Patients with Chronic Hepatitis B: This study evaluates the beneficial and harmful effects of using alpha-fetoprotein, ultrasonography, or both to screen for hepatocellular carcinoma in patients with chronic hepatitis B. Accessed July 6, 2022.
AASLD Practice Guidelines: The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: This article provides guidance for diagnosing and managing nonalcoholic fatty liver disease, rather than guidelines. Guidance, developed by a panel of experts, is intended to help clinicians understand and implement the most recent evidence. It includes guidance for screening, initial evaluation, evaluation for fibrosis, use of biopsy, and specific treatment. Accessed July 6, 2022.
