Overview of Chronic Hepatitis

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 Hepatitis D Hepatitis D is caused by a defective RNA virus (delta agent) that can replicate only in the presence of hepatitis B virus. It occurs uncommonly as a coinfection with acute hepatitis B or as... read more 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:

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.

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:

Primary biliary cholangitis Primary Biliary Cholangitis (PBC) Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more (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, including isoniazid, methotrexate, methyldopa, nitrofurantoin, tamoxifen, amiodarone, and rarely acetaminophen, can cause chronic hepatitis. The mechanism varies with the drug and may involve altered immune responses, development of steatohepatitis, cytotoxic intermediate metabolites, or genetically determined metabolic defects.

Less often, chronic hepatitis results from alpha-1 antitrypsin deficiency Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin deficiency is congenital lack of a primary lung antiprotease, alpha-1 antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults.... read more , celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more , a thyroid disorder, hereditary hemochromatosis Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more , or Wilson disease Wilson Disease Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion... read more .

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 Diagnosis reference 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... read more ]). 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 Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more (NAFLD).

Alkaline phosphatase is usually normal or only slightly elevated but is occasionally markedly high, particularly in primary biliary cholangitis Primary Biliary Cholangitis (PBC) Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more .

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 Hepatitis B Serology* and Hepatitis C Serology Hepatitis C Serology ). Unless these tests indicate viral etiology, further testing is required.

The next tests done include

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).

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 Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more and even portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in developed countries), schistosomiasis (in endemic areas), or hepatic vascular abnormalities... read more .

If the cause of hepatitis is identified, noninvasive tests (eg, ultrasound elastography, serum markers) can be done to assess the degree of liver fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced, degraded deficiently, or both. The trigger... read more .

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 Cryoglobulinemia Conditions that cause an abnormal protein content in the blood, typically in the form of immunoglobulins, can affect vascular fragility and lead to purpura. (See also Overview of Vascular Bleeding... read more 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 Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more 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.)

Treatment goals for chronic hepatitis include treating the cause and, if cirrhosis and portal hypertension have developed, managing complications (eg, ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , encephalopathy Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more ).

Drugs that cause hepatitis should be stopped. Acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease. NSAIDs should also be avoided in patients with severe hepatic impairment.

Underlying disorders should be treated. Lifestyle changes should be recommended for patients with NAFLD Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more or alcohol-related liver disease. Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to... read more

Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more may be required for decompensated cirrhosis.

There are specific antiviral treatments for chronic hepatitis B Treatment Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more (eg, entecavir and tenofovir as first-line therapies) and antiviral treatments for chronic hepatitis C Treatment Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more (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.

(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 NASH Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more aims to

It may involve

(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 orally once a day, then tapered to the lowest dose that maintains aminotransferases at normal or near-normal levels. To prevent long-term need for corticosteroid treatment, clinicians can transition to azathioprine 1 to 1.5 mg/kg orally once a day or mycophenolate mofetil 1000 mg twice a day after corticosteroid induction is complete and then gradually taper the corticosteroid. Most patients require long-term, low-dose, corticosteroid-free maintenance treatment.

Hereditary hemochromatosis is treated with phlebotomy.