Hepatitis C

Aka: Hepatitis C, HCV Infection

1. See Also
   1. Hepatitis C Antiviral Regimen
   2. Viral Hepatitis
   3. Bloodborne Pathogen Exposure
2. Epidemiology
   1. Mortality from Hepatitis C in the United States is more than any other infectious disease
   2. Effective treatment exists for those diagnosed, but many are undiagnosed
      1. Only 52% of estimated patients with Hepatitis C in U.S. have been diagnosed
      2. Only 37% of Hepatitis C patients have been diagnosed
      3. Worldwide, only 5% have been diagnosed, and <1% have been treated
      4. Chhatwai (2019) Aliment Pharmacol Ther 50(1): 66-74 [PubMed]
   3. Prevalence
      1. U.S. Population: 1.8% (4 to 6.5 million)
         1. Chronic hepatitis Prevalence is estimated at 3.7 million (2016)
         2. Prevalence is underestimated
            1. Undiagnosed patients infected in the 1960s and 1970s
            2. Opioid epidemic quadrupled acute infection rate ages 18-39 years from 2010 to 2018
      2. World Prevalence estimated at >185 million
         1. Associated with 350,000 deaths per year
      3. Intravenous Drug Abuse: 97% (some communities)
3. Pathophysiology
   1. Incubation 7-8 weeks
      1. HCV RNA found in blood within 3 weeks post-exposure
   2. Transmission by Blood Products and blood exposure
      1. Intravenous Drug Abuse (43-60% of acute cases in U.S.)
      2. Intravenous Immunoglobulin
      3. Transfusion
         1. Accounts for 85% transfusion associated hepatitis
         2. Clotting Factor transfusion before 1987
         3. Blood Product transfusion before 1992
         4. Risk from transfusion low after July 1992
            1. Now <1 case per 1,000,000 units transfused (2015)
      4. Tattoo needles
      5. Organ transplant (before July 1992)
      6. Longterm Hemodialysis
      7. Vertical transmission from mother to child
         1. Delivery method does not alter transmission rate
         2. Average rate: 6%
         3. HIV coinfection: 17%
      8. Needle Stick injury (4-10% rate of Infectivity)
         1. Seroconversion in 2200 healthcare workers per year
      9. No apparent parenteral risk factor in 40% of cases
   3. Transmission by other body fluid is less common
      1. Transmission to simple household contacts is rare
      2. No association with Lactation
      3. Sexual transmission is much less common
         1. Prevalence 1.5% in longterm partners
         2. Higher risk behaviors that raise transmission (blood to blood transmission)
            1. Multiple partners
            2. Early sex
            3. Non-Condom use
            4. Sex with associated Trauma or open lesions
            5. Comorbid Sexually Transmitted Disease
            6. Men who have Sex with Men (esp. if HIV positive)
            7. Anal intercourse
            8. Sex during Menses
            9. Shared sexual paraphernalia
4. Pathophysiology
   1. Similar to Flavivirus with RNA genome
   2. Similar viruses
      1. Yellow Fever virus
      2. DengueVirus
5. Findings: Signs and Symptoms
   1. Acute infection
      1. See Viral Hepatitis
      2. Asymptomatic in up to 70-80% of cases
      3. Symptoms in up to 35% of acute HCV Infection cases (onset 2 to 12 weeks after exposure)
         1. Malaise
         2. Weakness
         3. Anorexia
         4. Minor Fatigue
         5. Jaundice (uncommon in acute infection)
         6. Right Upper Quadrant Abdominal Pain or ache
         7. Nausea
         8. Arthralgias
   2. Chronic disease
      1. Most patients are asymptomatic
      2. Observe for signs of Cirrhosis
6. Differential Diagnosis
   1. Acute Hepatitis Causes
7. History: Screening Indications
   1. Universal screening for Hepatitis C age 18 to 79 years old at least once, regardless of risk factors (U.S., 2019)
   2. Screen all pregnant patients
   3. Screen once all patients born between 1945 and 1965 for Hepatitic C
   4. Screen periodically (up to annually) for continued high risk behavior
      1. Intravenous Drug Abuse
      2. HIV positive Men who have Sex with Men (unprotected)
   5. Other screening indications
      1. Received blood Clotting Factor concentrate before 1987
      2. Received Blood Transfusion or transplant before 1993
      3. Received blood from donor later found with HCV
      4. Received Hemodialysis
      5. Symptoms or signs of liver disease, or persistently elevated serum transaminases
      6. Mother with HCV at the time of delivery
8. Labs: Diagnosis
   1. See Hepatitis C Serology
   2. Hepatitis C Antibody Detection
      1. Detectable 4 to 10 weeks after exposure
      2. Positive in 97% of HCV Infections at 6 months
   3. Screening: EIA for Anti-HCVAntibody
      1. Third generation enzyme linked immunoabsorbent assay
         1. Test Sensitivity and Test Specificity: 99%
      2. Negative
         1. Consider False Negative if Immunocompromised
         2. Repeat in 12 weeks if HCV exposure in prior 6 months
            1. Alternatively, HCV RNA may be obtained every 4-8 weeks for 6 months
      3. Positive
         1. Confirm with HCV RNA (see below)
   4. Screening: OraQuick HCV Rapid Antibody Test
      1. CLIA Waved point-of-care test
      2. Test Sensitivity: 94.1%
      3. Test Specificity: 99.5%
      4. Negative Predictive Value: 99.9%
      5. Positive Predictive Value: 72.7%
   5. Confirmation of positive xHCV: RT-PCR for HCV RNA
      1. HCV RNA indicates acute infection (present as early as 2 weeks after exposure)
      2. Start with qualitative PCR (more sensitive)
      3. Positive EIA xHCV with negative PCR HCV RNA suggests resolved
      4. Repeat in 1-2 months if negative
      5. Also indicated before initiating HCV therapy
   6. Viral Genotype
      1. Indicated before initiating HCV therapy
      2. Of 6 HCV Genotypes, types Ia, Ib, 2 and 3 account for 97% of U.S. HCV Infections
      3. HCV Genotypes 2 and 3 have better prognosis than HCV Genotype 1
9. Labs: Assessment of liver disease
   1. Liver Function Tests
      1. Serum Albumin
      2. ProTime (PT) with INR
      3. Partial Thromboplastin Time (PTT)
   2. Liver Transaminase (Indicate hepatocellular necrosis)
      1. Serum AST
      2. Serum ALT
         1. Increases by 8 to 10 weeks (range 2 to 21 weeks, mean 7 weeks) from onset
         2. Peak at 10 to 20 times normal upper limit
         3. Normal in up to one third of patients
   3. Comorbid Infections
      1. Human Immunodeficiency Virus Test (HIV Test)
      2. Anti-HAV (Hepatitis A VirusAntibody)
      3. Hepatitis B Surface Antigen (HBsAg)
   4. Other tests
      1. Serum Iron (for Hemochromatosis)
      2. Renal Function Tests
         1. Serum Creatinine
         2. Blood Urea Nitrogen (BUN)
10. Labs: Post-exposure to Hepatitis C Virus
    1. Indications
       1. Blood-borne Exposure to Hepatitis C positive source (xHCV positive with detectable HCV RNA)
    2. Protocol
       1. Baseline (at time of exposure)
          1. Hepatitis C Antibody
          2. Hepatitis C RNA
          3. Alanine Transaminase (ALT)
       2. Week 4-6 post-exposure
          1. Hepatitis C RNA
       3. Month 4-6 post-exposure
          1. Hepatitis C Antibody
          2. Hepatitis C RNA
          3. Alanine Transaminase (ALT)
11. Evaluation: Grading
    1. See Metavir Scoring System (liver fibrosis, Cirrhosis)
    2. Imaging (and advanced labs) to evaluate for fibrosis or Cirrhosis
       1. See Cirrhosis for interpretation
       2. Transient Elastography and AST to Platelet Ratio Index
       3. Fibrosis-4
       4. Fibrosure
12. Management: General
    1. See Prevention of Liver Disease Progression
    2. Avoid Alcohol
       1. Alcohol and Hepatitis C work synergistically
       2. Alcohol decreases response to Interferon therapy
    3. Avoid Hepatotoxins
    4. Chemical Dependency treatment for injection drug use (if indicated)
    5. Avoid iron supplements
    6. Maintain a Low Fat Diet
    7. Maintain a target Body Mass Index <25 kg/m2
    8. Target a Low Sodium Diet <2000 mg/day
    9. Vaccination (decreases Hepatitis C progression risk)
       1. Hepatitis A Vaccine
       2. Hepatitis B Vaccine
       3. Pneumococcal Vaccine and PrevnarVaccine
    10. Prevent transmission
        1. Do not share razors or ToothBrushes
        2. Cover skin lesions
        3. Do not donate Blood Products
        4. Use Condom protection for intercourse (esp. for multiple partners, Men who have Sex with Men)
13. Management: Antiviral Agents
    1. See Hepatitis C Antiviral Regimen
    2. Consider early treatment for Acute Hepatitis C (started within 4 weeks of onset)
       1. Improves prognosis and decreases risk of chronic infection
       2. Wiegand (2006) Hepatology 43(2): 250-6 [PubMed]
14. Management: HCV-Related Cirrhosis
    1. Refer for consideration of liver Transplantation (see below)
    2. Hepatocellular Carcinoma monitoring
       1. Obtain RUQ Ultrasound and a-fetoprotein every 6-12 months
    3. Esophageal Varices monitoring
       1. Obtain upper endoscopy every 1-2 years
15. Management: Liver Transplantation
    1. Hepatitis C is most common cause of liver transplant
    2. Post-transplant survival similar to other liver failure
       1. One year survival post-transplant: 84%
       2. Five year survival post-transplant: 68%
       3. Ten year survival post-transplant: 60%
    3. Predictors of poorer outcome
       1. Female liver donor
       2. Recipient over age 52 years
       3. Preoperative Serum Creatinine >1 mg/dl
       4. More urgent UNOS status
       5. Increased Serum AST and Serum ALT levels
    4. References
       1. Ghobrial (2001) Ann Surg 234:384-94 [PubMed]
16. Complications
    1. Cirrhosis (20 to 30% in 25 to 30 years)
       1. Individualized risk can be calculated (see below)
    2. Decompensated Cirrhosis (Ascites, Hepatic Encephalopathy, Portal Hypertension, Varices)
       1. One Year: 3.9%
       2. Five Years: 18%
       3. Ten Years: 29%
    3. Hepatocellular Carcinoma
       1. Annual risk: 2-4% if Cirrhosis present
       2. Five Years: 7%
       3. Ten Years: 14%
    4. Other associated conditions (Extrahepatic Manifestations)
       1. Diabetes Mellitus (four fold increased risk)
       2. Membranoproliferative Glomerulonephritis
       3. Idiopathic Pulmonary Fibrosis
       4. Thyroid Disorders (Hypothyroidism, Hyperthyroidism, Thyroiditis)
       5. Vascular Disease
          1. Cardiovascular Disease (Coronary Artery Disease)
          2. Cerebrovascular Disease
       6. Rheumatologic and Autoimmune
          1. Sjogren's Syndrome
          2. Rheumatoid Arthritis
          3. Cryoglobulinemic Vasculitis
       7. Dermatologic conditions
          1. Porphyria cutanea tarda
          2. Lichen Planus
          3. Cutaneous necrotizing Vasculitis
          4. Raynaud Phenomenon
          5. Necrolytic Acral Erythema
       8. Malignancy
          1. B-Cell Non-Hodgkin Lymphoma
          2. Monoclonal Gammopathy
17. Course
    1. Progression after acute HCV Infection
       1. Spontaneous resolution: 15-45% of cases
          1. HCV RNA undetectable at 6 months after acute HCV
          2. Decreased chance of spontaneous clearance in HIV Infection
          3. Factors favoring spontaneous clearance and resolution
             1. Younger age
             2. Jaundice
             3. Increase alanine transaminase level
             4. HBsAg positive
             5. Female gender
             6. HCV Genotype 1
             7. Specific host genes (e.g. IL28 gene)
       2. Chronic Hepatitis: 50 to 85% of cases
          1. HCV RNA present >6 months after acute HCV Infection
          2. Cirrhosis develops in 20% of chronic HCV after 20-30 years, with a 75% mortality
          3. Chronic HCV mortality is secondary to Cirrhosis, end-stage liver disease and hepatocellular cancer
    2. Survival
       1. One Year: 96%
       2. Five Years: 91%
       3. Ten Years: 79%
    3. Risk Factors for Progression to fibrosis and Cirrhosis
       1. Age over 40 to years at time of infection
       2. Duration of infection
          1. Median duration of infection to Cirrhosis: 30 years
          2. In up to one third, Cirrhosis delayed for >50 years
       3. Male gender
       4. Excessive Alcohol intake
          1. Marked risk at >50 grams/day
          2. Moderate risk
             1. Men: >40 grams/day
             2. Women: >20 grams/day (2 beers, 1 pint wine)
       5. Other risk factors
          1. HIV Infection
          2. Hepatitis BVirus Infection
          3. Immunosuppression
          4. Obesity
          5. Hepatotoxic Medications
          6. Nonalcoholic Steatohepatitis
18. Resources
    1. IDSA HCV Management Guidelines
       1. http://www.hcvguidelines.org
    2. Probablility of Cirrhosis in Patients with Hepatitis C
       1. http://www.aafp.org/afp/20031101/poc.html
19. References
    1. Gross (1998) Mayo Clin Proc 73(4):355-60 [PubMed]
    2. Maness (2021) Am Fam Physician 104(6): 626-35 [PubMed]
    3. Morton (1998) Ann Emerg Med 31:381-90 [PubMed]
    4. Heathcote (2000) N Engl J Med 343:1673-80 [PubMed]
    5. Ward (2004) Am Fam Physician 69(6):1429-40 [PubMed]
    6. Wilkins (2015) Am Fam Physician 91(12): 835-42 [PubMed]