(See also Causes of Hepatitis Causes of Hepatitis Hepatitis is inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more , Overview of Acute Viral Hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , 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
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.
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 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 .
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:
Intensity of histologic inflammation and necrosis (grade)
Inflammation and necrosis are potentially reversible. Fibrosis can be reversible if the cause is fully treated in patients who do not have 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 .
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 Symptoms and Signs 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 (eg, splenomegaly, spider nevi, palmar erythema)
Complications of cirrhosis (eg, 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 , variceal bleeding Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may bleed massively but cause no... read more , 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 Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more , liver cancer 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 )
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 Lichen Planus Lichen planus is a recurrent, pruritic, inflammatory eruption characterized by small, discrete, polygonal, flat-topped, violaceous papules that may coalesce into rough scaly plaques, often accompanied... read more , mucocutaneous vasculitis Cutaneous Vasculitis Cutaneous vasculitis refers to vasculitis affecting small- or medium-sized vessels in the skin and subcutaneous tissue but not the internal organs. Cutaneous vasculitis may be limited to the... read more , glomerulonephritis Overview of Nephritic Syndrome Nephritic syndrome is defined by hematuria, variable degrees of proteinuria, usually dysmorphic red blood cells (RBCs), and often RBC casts on microscopic examination of urinary sediment. Often... read more , porphyria cutanea tarda Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is a comparatively common hepatic porphyria affecting mainly the skin. Liver disease is also common. PCT is due to an acquired or inherited deficiency in the activity... read more , mixed cryoglobulinemia, and, perhaps, non-Hodgkin B-cell lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more . 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
Serum albumin, platelet count, and prothrombin time/international normalized ratio (PT/INR)
(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 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.
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 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
Autoantibodies (antinuclear antibody, anti–smooth muscle antibody, antimitochondrial antibody, liver-kidney microsomal antibody)
Serum transferrin saturation and ferritin
Alpha-1 antitrypsin level
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
Screening for complications
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.)
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 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 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 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 . The risk is also increased in other liver disorders (eg, HCV infection, 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]), but usually when cirrhosis or advanced fibrosis has developed.
Treatment of Chronic Hepatitis
Treatment of cause (eg, corticosteroids for autoimmune hepatitis, antivirals for HBV and HCV infection)
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.
Chronic hepatitis B and C
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.
Nonalcoholic steatohepatitis (NASH)
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
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 hyperlipidemias and insulin resistance
Stopping drugs associated with NASH (eg, amiodarone, tamoxifen, methotrexate, corticosteroids such as prednisone or hydrocortisone, synthetic estrogens)
Avoiding exposure to toxins (eg, pesticides)
No pharmacotherapy is currently recommended specifically for the treatment of NASH
(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.
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.
Consider entecavir or tenofovir as first-line therapies for chronic hepatitis B.
Treat chronic hepatitis C of all genotypes with interferon-free regimens of direct-acting antivirals.
Treat autoimmune hepatitis with corticosteroids and transition to maintenance treatment with azathioprine or mycophenolate mofetil.
Encourage diet and exercise for weight loss (10% if possible) in patients with nonalcoholic fatty liver disease (NAFLD).
Treat hereditary hemochromatosis with phlebotomy.
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.