- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- ACG - American College of Gastroenterology
- ALT - Alanine aminotransferase
- AST - Aspartate aminotransferase
- CDC - Centers for Disease Control and Prevention
- HCC - Hepatocellular carcinoma
- HCV - Hepatitis C virus
- IDSA - Infectious Diseases Society of America
- PegIFN - Pegylated interferon
- USPSTF - U.S. Preventive Services Task Force
- OVERVIEW OF HEPATITIS
- Overview
- Viral hepatitis occurs when a virus infects the liver. A number of viruses including cytomegalovirus, Epstein-Barr virus, adenovirus, and others can infect the liver, but it is not a common site of infection for these viruses. Viruses that always infect the liver are designated by the letters A - G, and they cause the majority of viral hepatitis cases.
- Hepatitis A
- Overview
- Discovered in 1973
- Common virus - before widespread vaccination, up to 33% of US population would test positive for exposure
- Infection route
- Fecal-oral route (fecal-contaminated objects or food-sources reaching mouth)
- Incubation period for Hepatitis A is 15 - 50 days (average 30 days)
- Virus is excreted in the feces 1-2 weeks before symptoms and for 1 week afterwards
- Symptoms
- In many cases, will have mild or no symptoms
- May cause abrupt onset of diarrhea, nausea and vomiting, fever, and aching
- Jaundice, enlarged liver, and elevated liver enzymes may occur
- Symptoms usually resolve in 1-2 weeks, and liver enzymes typically return to normal by 3-6 months
- Treatment
- Supportive
- Long-term effects
- Rare
- Vaccine
- Yes [1,3]
- Hepatitis B
- Hepatitis C
- Overview
- Formally referred to an "Non-A, Non-B virus"
- First cloned in 1989
- Common virus - worldwide infects about 180 million people
- Infection route
- Primary route of infection is blood-to-blood (needles, transfusions, etc.)
- Symptoms
- There are no symptoms in most cases
- Occasionally will have acute symptoms including jaundice, elevated liver enzymes, malaise, and nausea
- Treatment
- Very curable with modern therapy
- Long-term effects
- Cirrhosis and hepatocellular carcinoma
- Vaccine
- No [4]
- Hepatitis D
- Overview
- First described in 1977
- Hepatitis D is believed to infect 1% of the world's population. It is endemic in parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.
- Hepatitis D requires the presence of hepatitis B to replicate, so all patients with hepatitis D will also have hepatitis B
- Infection route
- The primary route of infection is blood-to-blood (needles, transfusions, etc.)
- IV drug abusers and men who have sex with men are at greater risk
- Symptoms / Diagnosis
- There are no symptoms in most cases
- Hepatitis D screening is performed with antibody testing (IgG), and a diagnosis is confirmed with hepatitis D RNA assays
- Treatment
- Pegylated interferon alpha for 12 months. Sustained response is low (25 - 30%), and relapse rates are high.
- Long-term effects
- Chronic hepatitis B/D infection progresses to cirrhosis in 70 - 80% of patients within 5 - 10 years. The risk of hepatocellular carcinoma is also increased compared to hepatitis B monoinfection.
- Vaccine
- Hepatitis B vaccination will help prevent [3,29]
- Hepatitis E
- Overview
- First identified in 1983
- More common in India and developing countries
- Infection route
- Fecal-oral route (fecal-contaminated objects or food-sources reaching mouth)
- Symptoms
- Brief period (1-2 weeks) of gastrointestinal symptoms including nausea, vomiting, abdominal pain, and jaundice
- May be asymptomatic in healthy patients
- In pregnant women, can cause severe infection including liver failure and death (10 - 25% of affected patients)
- Treatment
- Supportive in most
- Ribavirin and interferon may be used in immunosuppressed patients
- Long-term effects
- None in otherwise healthy patients
- May cause chronic infection with cirrhosis in immunosuppressed patients
- Vaccine
- None available
- Vaccines are being evaluated in trials [3,23]
- Hepatitis G
- Overview
- First identified in 1996
- Clinical importance of this virus is not well-defined
- Infection route
- Not completely defined
- Primary route of infection appears to be blood-to-blood (needles, transfusions, etc.)
- Symptoms
- Not well-defined
- Treatment
- None studied
- Long-term effects
- Not well-defined
- Vaccine
- No [5]
- PREVALENCE OF HEPATITIS C
- Hepatitis C infects an estimated 180 million people worldwide
- In the United States, the estimated prevalence of hepatitis C among adults is 0.93%. About 52% of infected individuals live in 9 states: California, Texas, Florida, New York, Pennsylvania, Ohio, Michigan, Tennessee, and North Carolina. Hepatitis C is the leading cause of death from liver disease and the number one indication for liver transplantation. [6,27]
- RISK FACTORS FOR HEPATITIS C
- IV drug abuse
- Number one risk factor in the U.S.
- Blood transfusion or organ transplant before 1992
- Blood and organs were not tested for hepatitis C before 1992
- Hemophiliacs who received clotting factors before 1987
- In 1987, processes to inactivate viruses were started
- Heterosexual intercourse
- The risk of transferring hepatitis C through heterosexual intercourse is low
- Studies of heterosexual couples who have been in long-term monogamous relationships where only one partner is infected have shown that the transfer rate is from 0 - 0.6% per year
- Current guidelines do not recommend that long-term monogamous couples (with one Hep C positive individual) use barrier protection to prevent hepatitis C transmission
- Individuals may choose to use barrier methods if they wish to lower the already negligible transmission rate [9]
- Perinatal (mother-to-child)
- Transmission rate for hepatitis C from mother-to-child during pregnancy range from 3 - 10%
- Maternal coinfection with HIV increases the transmission rate with some studies showing rates up to 25%
- Higher viral loads are associated with a greater risk of transmission
- There is no conclusive evidence that the mode of delivery ( C-section versus vaginal ) has an effect on transmission rates
- Longer rupture of membranes ( > 6 hours ) may increase the risk of transmission
- Breastfeeding (for up to one year) does not appear to increase the transmission rate [8,28]
- Tattoos and body piercings
- If performed under unsanitary conditions, tattoos and body piercings may transmit the virus
- Hemodialysis patients
- In the past, dialysis patients often received frequent blood transfusions which increased their risk for hepatitis C
- Patient-to-patient transfer of hepatitis C in dialysis units has occurred, but is rare today [10]
- SCREENING FOR HEPATITIS C
- CDC recommendations
- Anyone who has ever injected illicit drugs
- Anyone born between 1945 - 1965 (baby boomers)
- Recipients of clotting factors before 1987 (typically hemophiliacs)
- Recipients of blood transfusions before 1992
- Recipients of organ transplants before 1992
- Chronic hemodialysis patients
- People with known exposure - ex. needlesticks in healthcare workers
- People with HIV infection
- Children born to hepatitis C positive mothers [14]
- USPSTF recommendations
- The USPSTF recommends screening all adults 18 - 79 years old for hepatitis C. Most adults only need to be screened once. Patients with ongoing risk factors should be screened periodically.
- AASLD, IDSA, ACG
- In addition to the CDC recommendations above, the AASLD, IDSA, and ACG recommend testing the following people:
- Current sexual partners of hepatitis C infected individuals
- People with unexplained elevated liver enzymes
- Healthcare workers with a mucosal exposure to hepatitis C-positive blood [6]
- DIAGNOSIS
- Exposure vs chronic infection
- When a person is exposed to hepatitis C, one of two things can happen:
- Scenario 1 - The immune system clears the infection and it is gone (about 15 - 45% of the time)
- Scenario 2 - The virus is able to infect the liver and a chronic infection is established (about 55 - 85% of the time) [6]
- Hepatitis C antibodies
- In both scenarios above, antibodies to hepatitis C will develop
- The test will turn positive 4 - 10 weeks after exposure in most patients
- The test will be positive in > 97% of patients 6 months after exposure [14]
- Hepatitis C viral load
- In Scenario 1, hepatitis C viral load will be detectable starting 2-3 weeks after exposure and remain detectable for 8 -16 weeks before becoming undetectable [6]
- In Scenario 2, hepatitis C viral load will remain detectable greater than 16 weeks after exposure [14]
- Exception
- There is one exception to the above rules if tests are done soon after exposure (between 2 - 10 weeks):
- Hepatitis C viral load may be positive and antibodies negative
- Testing exposed newborns
- Hepatitis C antibodies
- Mothers with hepatitis C infection will pass their antibodies on to their infants during pregnancy
- These antibodies will persist in the infant for up to 2 years in some cases
- In one study, maternal hepatitis C antibodies were present in uninfected infants at the following time points:
- Birth - 96.8%
- 6 months - 85%
- 9 months - 50%
- 12 months - 15.3%
- 18 months - 1.6%
- 24 months - 1.0% [8]
- Professional guidelines
- Current guidelines recommend antibody testing of infants born to HCV positive mothers at 18 months of age or later (not sooner) [14]
- Hepatitis C viral load (HCV RNA)
- Maternal HCV RNA may be present in a newborn at birth
- After birth, HCV RNA appears to quickly disappear in uninfected infants, but remains in infected infants [8]
- Professional guidelines
- Newborns may be tested for HCV RNA after 2 months of age
- The test should be repeated in 2 months regardless of the results [14]
- NATURAL COURSE OF UNTREATED HCV
- Cirrhosis
- Over the course of 25 - 30 years of infection, approximately 5 - 25% of HCV-infected individuals will develop cirrhosis [6]
- Women and children have a lower risk of cirrhosis with rates of 1 - 3% over 20 - 30 years [6,7]
- Other factors that increase the risk of cirrhosis include:
- Advanced age
- Obesity
- Alcohol abuse
- Hepatitis B infection
- HIV infection
- Hemochromatosis (iron storage disease)
- Hepatocellular carcinoma (HCC)
- Patients who develop cirrhosis from HCV have an annual incidence of hepatocellular carcinoma of 1 - 4% [7]
- See post-treatment surveillance for recommendations on monitoring patients for HCC
- Successful treatment of hepatitis C appears to decrease the risk of HCC. The cohort study detailed below followed the incidence of HCC in a group of veterans who were treated for HCV.
- A retrospective cohort study published in Hepatology followed 33,005 veterans who received treatment for hepatitis C of whom 10,817 were treated successfully
- After 30,562 person-years of follow-up, the following was seen:
- Patients with successful treatment (annual incidence of HCC): 0.3%
- Patients with successful treatment and cirrhosis (annual incidence of HCC): 1.39%
- Patients treated unsuccessfully (annual incidence of HCC): 1.3%
- Cirrhosis, successful treatment after the age of 64, diabetes, and genotype 3 infection were all significant risk factors for HCC in multivariate adjusted models
- LAB TESTS IN HEPATITIS C
- Hepatitis C antibody test
- The hepatitis C antibody test is the primary test used to screen for hepatitis C infection
- The test detects antibodies in the blood to hepatitis C virus
- The test has a very high sensitivity and specificity (> 95% in high-risk populations) [11]
- The test will turn positive 4 - 10 weeks after exposure in most infected patients
- The test will be positive in > 97% of infected patients at 6 months after exposure [14]
- If a person is exposed to hepatitis C, they will form hepatitis C antibodies even if the virus is cleared and no long-term infection occurs
- A positive antibody test does not mean a chronic infection is present
- A hepatitis C viral load is needed to confirm actual virus in the blood (chronic infection)
- Hepatitis C viral load
- Also referred to as "HCV RNA PCR," "Viral Quant," "HCV RNA"
- Hepatitis C is an RNA virus meaning it has ribonucleic acid in its nucleus
- The hepatitis C viral load test measures the amount of hepatitis C RNA present in the blood
- The test has a very high specificity (98-99%) and can measure virus levels down to 12 IU/ml in some assays
- A positive viral load means that hepatitis C virus infection is present [6]
- The test will turn positive 2 - 3 weeks after exposure [14]
- Some people may clear the infection and develop undetectable viral loads. See exposure vs chronic infection above
- Hepatitis C genotype
- A genotype is a particular group of genes that make up an organism
- The hepatitis C virus has six different genotypes and genotype 1 has two subtypes, a and b
- Hepatitis C genotypes are important because they predict how the virus will respond to therapy
- Genotype 1 (subtypes 1a and 1b)
- Most common genotype worldwide and most common in U.S. (70 - 80% of cases)
- Subtype 1a is more common in the U.S., and subtype 1b is more common in Europe
- Genotypes 2 and 3
- Genotypes 2 and 3 are the second most common in the U.S. (20 - 30% of cases)
- Genotype 4
- Common in the Middle East and Africa (uncommon in North America)
- Genotypes 5 and 6
- Not commonly seen
- Liver enzyme test (ALT, AST)
- Liver enzyme tests are used to detect inflammation in the liver (see AST and ALT for more)
- Patients with hepatitis C and normal liver enzymes are less likely to develop liver fibrosis, but fibrosis still occurs in 5 - 30% of these patients
- In the past, liver enzyme levels were used to help select patients for treatment. With newer, less toxic and more effective therapies, liver enzyme values are no longer a part of treatment recommendations
- Liver biopsy
- Liver biopsy with histology is the "gold standard" for measuring the severity of liver damage caused by hepatitis C
- In the past, liver biopsy was sometimes recommended when deciding which patients to treat. With newer, less toxic and more effective therapies, liver biopsy is no longer a part of treatment recommendations
- WHOM TO TREAT
- The AASLD/IDSA guidelines currently recommend that all patients with HCV infection be treated as long as they do not have a short life expectancy that cannot be increased with HCV therapy, liver transplantation, or another directed therapy
- See AASLD recommendations for more
- CURRENT TREATMENT RECOMMENDATIONS
- EXTRAHEPATIC (NONLIVER) EFFECTS OF HEPATITIS C
- Mixed cryoglobulinemia vasculitis (MCV)
- Physiology
- HCV is associated with a syndrome called mixed cryoglobulinemia vasculitis (MCV)
- Cryoglobulinemia refers to a syndrome where antibodies produced in response to HCV form complexes with the virus or parts of the virus
- The antibody-HCV complexes then deposit themselves in the walls of blood vessels
- These deposits may lead to inflammation of the blood vessel (vasculitis)
- Occurs in 19 - 50% of patients with HCV
- Symptoms
- MCV typically has no symptoms (> 85% of patients)
- When symptoms do occur, one of the following is typically seen:
- Vasculitis (palpable purpura)
- presents as red or purple bumps on the skin that do not blanch when pressed (18 - 33% of patients)
- Fatigue (35-54%)
- Muscle and joint aches (35-54%)
- Dry eyes and mouth (10 - 25%)
- Neuropathy (11-30%)
- Treatment
- Successful treatment of HCV typically makes the condition resolve
- For severe disease, plasmapheresis or immunological agents like rituximab (Rituxan®) may be used [19]
- Immune thrombocytopenia (ITP)
- Immune thrombocytopenia is a condition where autoimmune antibodies form against platelets. Platelet-antibody complexes are then removed by the spleen leading to a decrease in platelets.
- Hepatitis C infection is a major risk factor for ITP and is thought to account for up to 20% of ITP cases
- HCV antibodies that cross-react with platelet GPIIIa antigens and B-cell activation are possible mechanisms [26]
- Kidney disease
- Physiology
- HCV is associated with kidney disease
- If vasculitis from mixed cryoglobulinemia develops, it may affect the kidneys and lead to glomerulonephritis (inflammation and damage of the glomerulus)
- Glomerulonephritis can also occur when mixed cryoglobulinemia is not present
- All patients with chronic kidney disease should be screened for HCV
- Symptoms
- Decreased kidney function
- Protein in the urine
- Blood in the urine
- Treatment
- If glomerulonephritis is from mixed cryoglobulinemia, then treatment of HCV is recommended [19]
- Lymphoma
- Patients with HCV infection have a higher risk of developing lymphoma, particularly B-cell non-Hodgkin lymphoma [19]
- Diabetes and insulin resistance
- Patients with HCV may be at an increased risk for developing diabetes or insulin resistance [19]
- Sicca syndrome
- Sicca syndrome is an autoimmune syndrome that affects the lacrimal and salivary glands. Glandular autoantibodies cause inflammation and a loss of secretions which leads to dry mouth and dry eyes.
- Sicca syndrome has been reported in 9 - 67% of patients with HCV depending on the study
- Treatment of HCV does not appear to improve sicca syndrome [19]
- Joint pain
- Joint pain is common in HCV (up to 23% of patients). The pathology behind HCV-induced joint pain has not been determined but may be related to mixed cryoglobulinemia.
- Patients with HCV-induced joint pain often have a positive rheumatoid factor (50 - 80% of cases), but HCV infection alone is associated with a positive rheumatoid factor, so the significance of this is unclear [19,20]
- Autoimmune antibodies
- HCV infection often leads to the production of autoimmune antibodies that are seen in other diseases
Autoimmune antibodies in hepatitis C | |
---|---|
Antibody | Presence in HCV-infected people |
Antinuclear antibodies (ANA) | 17 - 41% |
Anti-smooth muscle cell | 9 - 40% |
Antithyroglobulin | 8 - 13% |
Anticardiolipin antibodies | 20 - 27% |
Rheumatoid factor | up to 71% |
- POST-EXPOSURE PROPHYLAXIS
- Overview
- The risk of HCV transmission from percutaneous and mucocutaneous exposure is 0.2% and 0%, respectively. Given the low transmission rate, the CDC does not recommend post-exposure prophylaxis with medications.
- Testing (CDC recommendations)
- All initial testing should be done as soon as possible, preferably within 48 hours
- Source patient
- Nucleic acid testing (viral load) is preferred. If nucleic acid testing is not available, HCV antibody test should be performed.
- If the nucleic acid test or the antibody test is negative, no further testing is necessary
- Detectable nucleic acid levels usually occur within 1 - 2 weeks after exposure. Positive antibody tests occur 4 - 10 weeks after exposure.
- Healthcare professional (if source patient is positive)
- Baseline test: Perform baseline HCV antibody test with reflex to nucleic acid test (viral load) if positive
- 3 - 6 weeks post-exposure: Perform nucleic acid test 3 - 6 weeks after exposure
- 4 - 6 months post-exposure: Perform HCV antibody test with reflex to nucleic acid test (viral load) if positive [3]
- Testing (UCSF)
- The University of California at San Francisco (UCSF) provides recommendations on lab testing after occupational HCV exposure at the link below
- They also offer free, rapid expert consultation by phone - UCSF consultation
- BIBLIOGRAPHY
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- 28 - PMID 23437438 - Reducing Risk for Mother-To-Infant Transmission of Hepatitis C Virus: A Systematic Review for the U.S. Preventive Services Task Force, Annals of Internal Medicine (2013)
- 29 - PMID 35696255 - A Patient With Jaundice and Malaise, JAMA (2022)