Overview of Chronic Hepatitis

The most common causes of chronic hepatitis are

• Hepatitis B virus

• Hepatitis C virus

• Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH)

• Alcohol-related liver disease

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% to 85% of cases of HCV infection become chronic (1). 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.

Criteria for the diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) include the presence of steatosis in the liver in the setting of at least 1 of the following risk factors (2):

• Overweight or obesity

• Dyslipidemia

• Insulin resistance

• Hypertension

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of MASLD that causes chronic hepatitis.

Alcohol-related liver disease (a combination of fatty liver, diffuse liver inflammation, and liver necrosis) results from excess alcohol consumption.

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 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.

1. 1. National Institutes of Diabetes and Digestive and Kidney Diseases: Hepatitis C. Accessed June 21, 2024.

2. 2. Rinella ME, Lazarus JV, Ratziu V, et al: A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 78(6):1966-1986, 2023.  doi: 10.1097/HEP.000000000000052

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 metabolic dysfunction-associated steatotic liver disease (MASLD).

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.

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 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 serum ferritin suggest hereditary hemochromatosis and should be followed by genetic testing for the hemochromatosis gene (HFE).

Serum albumin, platelet count, and PT should be measured to assess liver function and disease severity; low serum albumin, a low platelet count, or prolonged PT may suggest 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.

Clinical Calculators

Autoimmune Hepatitis Diagnostic Criteria

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

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 (2).

1. 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. 

2. 2. Aghoram R, Cai P, Dickinson JA: Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B. Cochrane Database Syst Rev 2012(9):CD002799, 20212 doi: 10.1002/14651858.CD002799.pub2

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 MASLD or alcohol-related liver disease.

Liver transplantation may be required for decompensated cirrhosis.

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 medications 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 medications 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.

(See also The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Disease.)

Treatment of MASH 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

• Treating concomitant metabolic risk factors such as hyperlipidemia and insulin resistance

• Avoiding exposure to toxins (eg, pesticides)

(See also practice guidelines from the American Association for the Study of Liver Diseases, Diagnosis and Management of Autoimmune Hepatitis.)

Corticosteroids,

Hereditary hemochromatosis is treated with phlebotomy.