A 30-year-old male presents to the physician for a one-week history of fever

A 30-year-old male presents to the physician for a one-week history of fever, generalized body
pain, and vomiting. He appears pale and fatigued. A complete blood count is ordered and is
unremarkable. He is recommended to take acetaminophen and drink copious fluids. One week later
the fever persists. He reluctantly discloses to the physician that he recently tried IV drugs and had
unprotected sex at a party. Hepatitis B, C, and HIV tests are ordered. Antibody testing comes back
positive for hepatitis C. Polymerase chain reaction test (PCR) detects HCV RNA genotype 3.
Which of the following is the most likely mechanism of hepatocellular injury in this patient?

  • A) Direct viral cytotoxicity (Direct viral damage)
  • B) Antibody-dependent cell-mediated cytotoxicity
  • C) T cell-mediated hepatocellular apoptosis
  • D) Th-inducing BTB/POZ domain-containing Kruppel-like zinc-finger transcription factor
  • (ThPOK)

0 voters


Transmission of hepatitis C
• Hepatitis C is most frequently acquired via contaminated blood products or intravenous drug
• The risk of infection from a single needle-stick injury is 5-15% but may depend on the size of
the inoculation.1
Risk of transmission from sexual contact among heterosexual couples is low
• “Among 500 couples and 8377 person-years of sexual contact, the HCV Partners Study found a
low prevalence of HCV infection among partners, with a maximum of 1.2% (95% CI: 0.2%–
2.2%) of infections potentially attributable to sexual contact.”2
• “The maximal incidence of HCV infection was 7.2 per 10,000 person-years (95% CI: 1.3–13.0),
and maximal risk per sexual contact was 1 per 380,000 (95% CI: 1/600,000–1/280,000).”2
• “Overall, available data indicate that HCV transmission by sex is reassuringly low, and the
HCV Partners Study provides the numerical context to counsel HCV-infected persons in
monogamous partnerships.”2
• “In contrast to hepatitis B, the risk of sexual transmission of HCV has always been considered
low. This low risk was confirmed by a recent study among 500 anti‐HCV‐positive, HIV‐
negative persons and their long‐term HCV‐negative heterosexual partners, reporting a
maximum incidence rate of HCV transmission by sex of 0.07% per year or one infection per
190,000 sexual contact…”3
Hepatocellular injury due to hepatitis C likely not due to direct viral damage
• “Although the exact mechanisms inducing the hepatic injury in chronic hepatitis C infection are
still not completely elucidated, the evidence of a direct cytopathic viral effect is sparse. The
overall majority of experimental studies and clinical observations among patients instead favor
immune-mediated hepatocellular damage.”4

• “In immune competent hosts, there is little evidence that direct cytopathicity plays a significant
role in liver cell injury.”5
Hepatocellular injury due to hepatitis C is believed to be T cell-mediated
• “The host immune response, in its attempt to clear the virus from the liver, contributes to the
hepatocellular damage (chronic hepatitis) seen in the majority of chronically infected patients.”5
• “In HCV infection, upregulation of CD95 in hepatocytes as well as induction of CD95L
expression in T-lymphocytes have been found to correlate with the severity of inflammation.”6
• “The prevalence of CD95 in HCV antigen-positive hepatocytes was significantly higher than in
uninfected cells. Moreover, it has been suggested that the degree of CD95 expression correlates
with hepatocyte apoptosis.”6
• “It has been proposed that CD95L-positive T-lymphocytes interact with CD95-bearing
hepatocytes which results in liver cell apoptosis.”6
• “Cytotoxic T lymphocyte-mediated lysis of virus-infected host cells may lead to clearance of
the virus or, if incomplete, to viral persistence and eventually chronic tissue injury.”7
Hepatocellular injury due to hepatitis A, B, and E is due to immune-mediated damage.
Hepatitis D may cause direct viral cytotoxic effects in addition to heralding immune-mediated
damage.8, 9, 10, 11, 12, 13
Regarding hepatitis A
• “In particular, severe CD8+ T cell-mediated liver injury is known as a primary cause of tissue
damage in hepatitis A virus (HAV) infection.”8
Regarding hepatitis B
• “It is generally accepted that the hepatitis B virus is not cytopathic and that liver cell damage in
chronic HBV infection is dependent on the host’s immune response directed at viral and selfantigens on the surface of infected hepatocytes.”9
• “In these patients, both T and non-T cells from peripheral blood have been shown to be
cytotoxic to autologous hepatocytes.”9
Regarding hepatitis D
• “It has been postulated that hepatocyte injury resulting from infection with hepatitis D virus
may be caused by a direct virus cytotoxicity in contrast to immune-mediated injury associated
with hepatitis B virus.”10
• “Hepatic cell death occurs due to direct cytotoxic effects of hepatitis D virus or a host-mediated
immune response.”11
• “HDV may cause hepatic failure through direct cytotoxicity caused by the S-HDAg or inducing
an exaggerated immune response leading to the destruction of hepatocytes by cytotoxic T