Incidence

1. The World Health Organization (WHO) estimates that more than 185 million individuals are chronically infected with HCV worldwide.
2. Of every 100 people infected with HCV, approximately:
   1. 75 to 85 will go on to develop chronic infection.
   2. 10 to 20 will go on to develop cirrhosis over a period of 20 to 30 years.
   3. Rates of progression to cirrhosis are increased in the presence of a variety of factors: males more than females, age greater than 50 years, alcohol, nonalcoholic fatty liver disease (NAFLD), HBV or HIV coinfection, immunosuppressive therapy.
3. Among patients with cirrhosis, there is:
   1. 1% to 5% annual risk of HCC.
   2. 36% annual risk of hepatitic decompensation, for which the risk of death in the following year is 15% to 20%.
4. Approximately 15% to 25% of people clear the HCV virus without treatment and do not develop chronic infection. Although they are no longer infected, they will still test positive for antibodies to HCV (anti-HCV):
   1. Predictors of spontaneous clearance include jaundice, elevated alanine transaminase (ALT) level, hepatitis B surface antigen (HBsAg) positivity, female sex, younger age, HCV genotype 1, and host genetic polymorphisms, most notably those near the IL28B gene.
5. HCV infection becomes chronic in approximately 75% to 85% of cases. A person infected with HCV mounts an immune response to the virus, but replication of the virus during infection can result in changes that evade the immune response. This may explain how the virus establishes and maintains chronic infection.
6. Seroprevalence rates among individuals vary according to their associated risk factors. The highest rates occur in persons with large or repeated direct percutaneous exposure to blood or blood products, such as intravenous (IV) drug users and patients with hemophilia who have received multiple blood transfusions.
7. Seroprevalence among pregnant women in the United States has been estimated at 1% to 2%. Maternal–fetal (vertical) transmission only ranges from 3% to 10%. Risk for transmission is highest among women with a high viral load at delivery. Maternal coinfection with HIV has been associated with increased risk of perinatal transmission of HCV RNA.
8. Serum anti-HCV antibody and HCV RNA have been detected in colostrum. However, although only a limited number of patients have been studied, the rate of transmission among breastfed infants is the same as among bottle-fed infants.

Pathogenesis

1. HCV is a small, single-stranded RNA virus with a lipid envelope and is a member of the Flavivirus family. It is a bloodborne virus and the most common modes of infection are through exposure to small quantities of blood injection drug use, unsafe injection practices, and transfusion of unscreened blood and blood products.
2. The WHO also notes that one of the most common transmissions is in the reuse or inadequate sterilization of medical equipment, especially syringes and needles in healthcare settings.
3. Sexual transmission of HCV is uncommon except with high-risk behavior.
4. The incubation period averages 6 to 7 weeks, with a range of 2 weeks to 6 months. The time from exposure to the development of viremia generally is 1 to 2 weeks.

Predisposing Factors

All people with HCV-RNA in their blood are considered to be infectious. The following groups are at high risk for HCV infection and should be tested:

1. IV drug users who have shared needles.
2. Intranasal cocaine users, presumably resulting from epistaxis and shared equipment.
3. Hemophiliacs, hemodialysis patients, and those who received blood transfusions before 1992.
4. Recipients of solid organ transplants prior to 1992.
5. Healthcare workers with percutaneous exposures.
6. Individuals with multiple sexual partners.
7. Transmission among contacts living with infected persons may occur with percutaneous or mucosal exposure to blood.
8. Infants of infected mothers, by vertical transmission.
9. HCV is more common in males than females.
10. Tattooing, body piercing, and acupuncture with unsterile equipment.
11. HIV.
12. Incarceration.

Common Complaints

1. Chronic HCV—asymptomatic unless there is progressive inflammation and complications from cirrhosis.
2. Malaise.
3. Anorexia.
4. Nausea.
5. Myalgia.
6. Fever.
7. Abdominal pain.

Other Signs and Symptoms

1. Jaundice (occurs in fewer than 20% of patients).
2. Hepatomegaly is present in one third of patients with an acute infection.
3. Ascites.
4. Spider nevi.
5. Dark urine.
6. Clay-colored stools.

Subjective Data

1. Review duration, onset, and severity of symptoms.
2. Ask the patient about other family members and sexual contacts with similar symptoms.
3. Review family history of hepatocellular carcinoma (HCC).
4. Review the patient’s history of blood transfusions, tattoos, incarceration, IV drug use, and alcohol abuse.
5. Ask the patient about occupational exposure to blood and bodily secretions.
6. Ask about high-risk sexual practices.
7. Inquire about recent international travel.
8. Establish the patient’s usual weight; note amount of any weight lost and over what length of time.
9. Review for a history of variceal bleeding.
10. Ask if the patient has been treated for any type of hepatitis:
    1. How long ago was the patient treated?
    2. Did the patient complete therapy? If not, why?
    3. What was the patient’s response to therapy (i.e. nonresponder, relapser, etc.)?
11. Has the patient had any testing for cirrhosis/liver biopsy? What testing and when?
12. Review HIV status.

Physical Examination

1. Check temperature (acute infection), pulse, respirations, blood pressure (BP), height and weight to calculate body mass index (BMI).
2. Inspect:
   1. Observe general appearance, muscle wasting, edema, and demeanor. Administer a depression self-assessment tool at each visit when on HCV therapy.
   2. Inspect the skin for jaundice, rash, dehydration, palmar erythema, excoriations, spider nevi, and tattoos/piercings.
   3. Inspect the eyes for yellow sclera.
   4. Inspect mucous membranes and nail beds for clubbing and cyanosis.
   5. Inspect for gynecomastia and small testes.
3. Auscultate:
   1. Auscultate lung fields and heart.
   2. Auscultate all quadrants of the abdomen and evaluate for abdominal bruit.
4. Percuss the abdomen.
5. Palpate:
   1. Palpate all quadrants of the abdomen for masses, liver enlargement or tenderness, characteristics of cirrhosis, and hepatosplenomegaly, which occurs in about 10% of cases.
   2. Palpate the lymph nodes for lymphadenopathy and enlarged parotid.

Diagnostic Tests

1. Complete blood count (CBC) with platelets.
2. Complete liver panel:
   1. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT).
   2. Total Bilirubin.
   3. Prothrombin Time (PT)/International normalized ration (INR).
   4. Albumin.
3. Alkaline phosphatase (ALP).
4. Other viral infection markers, especially Hepatitis B virus (HBV) and HIV.
5. Alpha-fetoprotein (AFP; rule out other causes of liver disease).
6. Gamma-glutamyl transferase (GGT).
7. Thyroid profile.
8. A1C.
9. After HBV confirmation:
   1. HBV genotype.
   2. HBVDNA viral load.
10. Serum fibrosis panel:
    1. AST-to-platelet ratio index (APRI) used for estimating hepatic fibrosis. Online calculator can be found at: www.hepatitisc.uw.edu/page/clinical-calculators/apri.
    2. Fibrosis-4 (FIB-4) is an index for estimating hepatic fibrosis based on a calculation derived from AST, ALT, platelet concentrations, and age. Online calculator can be found at: www.hepatitisc.uw.edu/page/clinical-calculators/fib-4.
    3. FibroTest (FibroSure)—commercial biomarker test that uses the results of six blood markers to estimate hepatic fibrosis.
11. Imaging:
    1. Ultrasonography: FibroScan—Transient shear wave elastography measures liver stiffness as a surrogate for fibrosis.
    2. CT or MRI to help exclude biliary obstruction.
12. Liver biopsy to assess the severity of disease.
13. Pregnancy testing before and during antiviral therapy.
14. The in-depth initial and follow-up testing for HCV is located at the American Association for the Study of Liver Disease (AASLD) and Infectious Diseases Society of America (IDSA) website, www.hcvguidelines.org/evaluate. These guidelines are dynamic; therefore the website should be accessed frequently.

Differential Diagnoses

1. Hepatitis C.
2. Hepatitis A.
3. Hepatitis B.
4. Alcoholic liver disease (ALD).
5. Drug toxicities.
6. Opportunistic infections associated with HIV infection.
7. Infectious hepatitis (viral, bacterial, fungal, and parasitic).
8. Autoimmune diseases.

Plan

1. See Section III: Patient Teaching Guide “Jaundice and Hepatitis:”
   1. Discuss the possibility of transmission to others, and tell the patient to refrain from donating blood, organs, tissues, or semen and from sharing toothbrushes and razors.
   2. All patients with chronic HCV should be immunized against hepatitis A and hepatitis B.
   3. Counsel the patient to avoid hepatotoxic medications and alcohol:
      1. Recommend abstinence or minimal alcohol consumption. More than seven drinks of alcohol per week for women and more than 14 drinks per week for men are associated with an increase of cirrhosis and HCC.
   4. Any blood spills should be cleaned using a 1:10 dilution of bleach to water for disinfecting the area. Gloves should be worn when cleaning up any blood spills.
   5. The WHO recommends that alcohol screening and behavioral interventions for people with moderate to high alcohol intake should be instituted.
   6. The Centers for Disease Control and Prevention (CDC) recommends that anyone born between the years of 1945 and 1965 be tested for HCV one time.
2. Pharmaceutical therapy is aimed at inhibiting HCV replication and eradicating infection. Pharmaceutical regimens are quickly evolving as new medications come to the market. The AASLD and IDSA guidelines break down therapy and management in detail by genotype/subtypes, presence of cirrhosis, whether a patient is treatment-naïve or treatment-experienced, and medications and length of therapy. The guidelines are located at www.hcvguidelines.org/contents. The guidelines also include the management of unique populations including patients with HIV/HCV coinfection, patients with decompensated cirrhosis, patients who develop recurrent HCV infection post–liver transplant, patients with renal impairment, kidney transplant patients, management of acute HCV infection, HCV in pregnancy and children, management of chronic HCV infection, HCV in people who inject drugs, men who have sex with men (MSM), and testing and treatment in correctional facilities.

Follow-Up

1. Refer to AASLD/IDSA current guidelines on testing, managing, and treating hepatitis C.

Consultation/Referral

1. Referrals include gastroenterologist, hepatologist, infectious disease, psychiatrist, endocrinologist, neurologist, hematologist, dietitian, and social workers.
2. Patients who are coinfected with HBV or HIV or have end-stage renal disease should be referred to and managed by a hepatologist, infectious disease provider, or gastroenterologist for treatment.

Individual Considerations

1. Pregnancy:
   1. Routine serologic testing of pregnant women for HCV infection is not recommended. Women with significant risk factors for HCV should be offered antibody screening.
   2. According to current guidelines of the U.S. Public Health Service and the American Academy of Pediatrics, maternal HCV infection is not a contraindication to breastfeeding. HCV-positive mothers should consider abstaining from breastfeeding if their nipples are cracked or bleeding.
   3. The method of delivery has not been shown to increase the risk of vertical transmission of HCV. Cesarean delivery is reserved for obstetric indications.
2. Adults:
   1. Infected persons with steady partners do not need to change their sexual practices. However, they should be informed of the possible risk of transmission and of what precautions to use to prevent transmission.
   2. Persons with multiple partners should be advised to reduce the number of partners and to use condoms to prevent transmission.
3. Geriatrics:
   1. As the population ages the cases of HCV will increase more in the elderly than in other age groups.
   2. There is substantial decrease in liver mass, in the number of hepatocytes, and in the portal blood flow, which results in alteration of metabolism. There are significant reductions up to 30% to 40% in parenchymal volume, liver blood flow, and perfusion.
   3. The elderly have a higher rate of mortality than younger patients, reflecting in part a higher prevalence of comorbid conditions such as diminished immune response, metabolic derangement, nutritional deficiencies, and greater cumulative exposure to environmental hepatotoxins.
   4. Older age is an independent factor associated with a lower likelihood of being considered for antiviral therapies:
      1. Adults over 60 have a higher prevalence of comorbidities, particularly cardiovascular, renal, pulmonary, and hematological diseases.
      2. Older adults are less likely to accept antiviral treatment.
      3. Discontinuation of therapy and reductions are more frequently required in this age group.
      4. Elderly adults have a faster progression to fibrosis.
   5. Liver transplant programs may have relative contraindication inclusion criteria for liver transplant for ages more than 65 to 70 years.

Resources

American Association for the Study of Liver Diseases: www.aasld.org.

American Liver Foundation: www.liverfoundation.org.

Centers for Disease Control and Prevention: www.cdc.gov/hepatitis.

Hepatitis and HIV: www.hivandhepatitis.com.

Hepatitis Foundation International: www.hepfi.org.

Immunization Action Coalition: www.immunize.org.

National Institute of Diabetes and Digestive and Kidney Diseases: www2.niddk.nih.gov.

Project Inform Information, Inspiration, and Advocacy for People with HIV/AIDS and Hepatitis C: www.projectinform.org (includes Spanish resources).

United Network for Organ Sharing: www.unos.org.

World Health Organization Guidelines for the screening, care, and treatment of persons with hepatitis C infection: www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en.