History
Thorough history can highlight relatively significant risk factors, including living in an endemic area, close personal contact with an infected person, men who have sex with men, travel to high-risk areas, drug use, known foodborne or waterborne outbreak, and homelessness.[21]Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices, 2020. MMWR Recomm Rep. 2020 Jul 3;69(5):1-38.
https://www.cdc.gov/mmwr/volumes/69/rr/rr6905a1.htm
http://www.ncbi.nlm.nih.gov/pubmed/32614811?tool=bestpractice.com
In about one third of reported cases, no risk factor is identified.[13]Centers for Disease Control and Prevention. Viral hepatitis surveillance report - United States, 2021. Aug 2023 [internet publication].
https://www.cdc.gov/hepatitis/statistics/2021surveillance/hepatitis-a.htm
History should also assess risk or history of other liver diseases such as hepatitis B and hepatitis C virus infections and/or cirrhosis, as concomitant acute hepatitis A virus (HAV) infection in these circumstances has a higher risk for progression to HAV acute liver failure.
Symptoms and signs
The incubation period averages 28 days (range 15-50 days).[1]Committee on Infectious Diseases, American Academy of Pediatrics; Kimberlin D, Barnett E, Lynfield R, et al. Hepatitis A. In: Red Book: 2021–2024 report of the Committee on Infectious Diseases. 32nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 2021.
Most infections in children ages <6 years are asymptomatic; possible symptoms include fever, nausea, anorexia, and malaise.[1]Committee on Infectious Diseases, American Academy of Pediatrics; Kimberlin D, Barnett E, Lynfield R, et al. Hepatitis A. In: Red Book: 2021–2024 report of the Committee on Infectious Diseases. 32nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 2021. Only 10% of infected children develop jaundice.[33]World Health Organization. Hepatitis A. July 2023 [internet publication].
https://www.who.int/news-room/fact-sheets/detail/hepatitis-a
In adults and older children, clinical course can be divided into preicteric phase and icteric phase.[2]Brundage SC, Fitzpatrick AN. Hepatitis A. Am Fam Physician. 2006 Jun 15;73(12):2162-8.
http://www.aafp.org/afp/20060615/2162.html
http://www.ncbi.nlm.nih.gov/pubmed/16848078?tool=bestpractice.com
The preicteric phase lasts 5-7 days characterized by abrupt onset of nausea, vomiting, abdominal pain, fever, malaise, fatigue, and headache. Relatively less common symptoms include arthralgias, myalgias, diarrhea, constipation, cough, pruritus, and urticaria.[19]Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev. 2001 Jan;14(1):38-58.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88961
http://www.ncbi.nlm.nih.gov/pubmed/11148002?tool=bestpractice.com
Physical signs may include right upper quadrant pain with tender hepatomegaly, splenomegaly, posterior cervical lymphadenopathy, evanescent rash, and bradycardia.[2]Brundage SC, Fitzpatrick AN. Hepatitis A. Am Fam Physician. 2006 Jun 15;73(12):2162-8.
http://www.aafp.org/afp/20060615/2162.html
http://www.ncbi.nlm.nih.gov/pubmed/16848078?tool=bestpractice.com
[19]Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev. 2001 Jan;14(1):38-58.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88961
http://www.ncbi.nlm.nih.gov/pubmed/11148002?tool=bestpractice.com
Within a few days to a week the icteric phase begins with dark urine, acholic stools, jaundice, and pruritus.[2]Brundage SC, Fitzpatrick AN. Hepatitis A. Am Fam Physician. 2006 Jun 15;73(12):2162-8.
http://www.aafp.org/afp/20060615/2162.html
http://www.ncbi.nlm.nih.gov/pubmed/16848078?tool=bestpractice.com
With the onset of jaundice the preicteric phase symptoms usually diminish. Jaundice peaks typically at 2 weeks.
Prolonged disease or acute liver failure
A minority of people (10% to 20%) have a prolonged or relapsing course. After initial infection, there is a remission with partial or complete resolution of symptoms and abnormal liver tests. Relapse typically occurs within 3 weeks and is milder than the initial infection. Immune-mediated manifestations (purpura, arthralgia, nephritis) may occur.[34]Glikson M, Galun E, Oren R, et al. Relapsing hepatitis A: review of 14 cases and literature survey. Medicine (Baltimore). 1992 Jan;71(1):14-23.
https://journals.lww.com/md-journal/Citation/1992/01000/Relapsing_Hepatitis_A_Review_of_14_Cases_and.2.aspx
http://www.ncbi.nlm.nih.gov/pubmed/1312659?tool=bestpractice.com
A prolonged course can last several months with persistent fever, pruritus, diarrhea, jaundice, weight loss, and malabsorption.[19]Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev. 2001 Jan;14(1):38-58.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88961
http://www.ncbi.nlm.nih.gov/pubmed/11148002?tool=bestpractice.com
[20]Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 14th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2021.
https://www.cdc.gov/vaccines/pubs/pinkbook/index.html
Acute liver failure occurs in <1% of patients, and is characterized by worsening jaundice, coagulopathy, and encephalopathy, due to severe impairment of hepatic functions, or severe necrosis of hepatocytes in absence of preexisting chronic liver disease.[35]Taylor RM, Davern T, Munoz S, et al. Fulminant hepatitis A virus infection in the United States: incidence, prognosis, and outcomes. Hepatology. 2006 Dec;44(6):1589-97.
http://www.ncbi.nlm.nih.gov/pubmed/17133489?tool=bestpractice.com
[36]Ajmera V, Xia G, Vaughan G, et al; the Acute Liver Failure Study Group. What factors determine the severity of hepatitis A-related acute liver failure? J Viral Hepat. 2011 Jul;18(7):e167-74.
http://www.ncbi.nlm.nih.gov/pubmed/21143345?tool=bestpractice.com
An excessive host immune response has been implicated.[36]Ajmera V, Xia G, Vaughan G, et al; the Acute Liver Failure Study Group. What factors determine the severity of hepatitis A-related acute liver failure? J Viral Hepat. 2011 Jul;18(7):e167-74.
http://www.ncbi.nlm.nih.gov/pubmed/21143345?tool=bestpractice.com
[37]Fujiwara K, Kojima H, Yasui S, et al. Hepatitis A viral load in relation to severity of the infection. J Med Virol. 2011 Feb;83(2):201-7.
http://www.ncbi.nlm.nih.gov/pubmed/21181913?tool=bestpractice.com
Diagnostic tests
Serum liver enzymes and bilirubin can be ordered as soon as clinical symptoms begin.[18]Kemmer NM, Miskovsky EP. Hepatitis A. Infect Dis Clin North Am. 2000 Sep;14(3):605-15.
http://www.ncbi.nlm.nih.gov/pubmed/10987112?tool=bestpractice.com
[19]Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev. 2001 Jan;14(1):38-58.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88961
http://www.ncbi.nlm.nih.gov/pubmed/11148002?tool=bestpractice.com
Aminotransferase levels may reach more than 10,000 units/L, although there is little correlation between level and disease severity. The serum alanine aminotransferase (ALT) is commonly higher than the serum aspartate aminotransferase (AST). While alkaline phosphatase level is usually elevated minimally, the bilirubin level is usually elevated to about 5-10 mg/dL.[38]Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis. 1995 Mar;171(suppl 1):S15-8.
http://www.ncbi.nlm.nih.gov/pubmed/7876641?tool=bestpractice.com
Blood urea nitrogen, serum creatinine, and prothrombin time (PT) may also be measured at baseline. Acute kidney injury has been reported in patients with HAV.[39]Shin SJ, Kim JH. The characteristics of acute kidney injury complicated in acute hepatitis A. Scand J Infect Dis. 2009;41(11-12):869-72.
http://www.ncbi.nlm.nih.gov/pubmed/19922071?tool=bestpractice.com
Patients with acute liver failure typically have a prolonged PT.
Tests for immunoglobulin M (IgM) anti-HAV and IgG anti-HAV can be ordered concurrently. Serum IgM anti-HAV antibodies are usually positive 5-10 days before onset of symptoms, peak during the acute or early convalescent phase of the disease, and decline to undetectable levels over 6 months.[1]Committee on Infectious Diseases, American Academy of Pediatrics; Kimberlin D, Barnett E, Lynfield R, et al. Hepatitis A. In: Red Book: 2021–2024 report of the Committee on Infectious Diseases. 32nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 2021.[20]Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 14th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2021.
https://www.cdc.gov/vaccines/pubs/pinkbook/index.html
[21]Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices, 2020. MMWR Recomm Rep. 2020 Jul 3;69(5):1-38.
https://www.cdc.gov/mmwr/volumes/69/rr/rr6905a1.htm
http://www.ncbi.nlm.nih.gov/pubmed/32614811?tool=bestpractice.com
Laboratory findings should be correlated with clinical features. Some asymptomatic patients may have previous HAV infection with prolonged presence of IgM anti-HAV. False-positive laboratory results and asymptomatic infection are both possible (more common in children ages younger than 6 years).[40]Centers for Disease Control and Prevention. Positive test results for acute hepatitis A virus infection among persons with no recent history of acute hepatitis: United States, 2002-2004. MMWR Morb Mortal Wkly Rep. 2005 May 13;54(18):453-6.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5418a1.htm
http://www.ncbi.nlm.nih.gov/pubmed/15889006?tool=bestpractice.com
IgG anti-HAV remains detectable for decades.
Reverse-transcriptase polymerase chain reaction to detect HAV RNA in stool, body fluids, serum, and liver tissue is available. It is rarely necessary but may be considered to detect very early cases or if HAV-IgM results are inconclusive.[1]Committee on Infectious Diseases, American Academy of Pediatrics; Kimberlin D, Barnett E, Lynfield R, et al. Hepatitis A. In: Red Book: 2021–2024 report of the Committee on Infectious Diseases. 32nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 2021.