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Clinical Correlation
Hepatitis C
Hepatitis C Virus: Morphology and Characteristics
Hepatitis C Virus
• Nucleic Acid: 9.6 kb ssRNA
• Classification: Flaviviridae,
Hepacivirus
40-60 nm • Genotypes: 1 to 6
• Enveloped
5’ 3’
c E1 E2 NS NS NS NS
ore 2 3 4 5
hypervariable
region
Hepatitis C Life Cycle
CD81?
www.rockefeller.edu/pubinfo/hepc.jpg
Prevalence
HCV - Epidemiology
Prevalence
HCV - Epidemiology
*Sexual transmission of HCV is not clearly understood. However, certain high risk sexual
behaviors have been associated with HCV transmission such as anal sex, sex with trauma, sex in
the presence of a sexually transmitted disease (STD), and sex without a condom.
Hepatitis C - Clinical
Features
Incubation period: Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice): 30-40% (20-30%)
Chronic hepatitis: 70%
Persistent infection: 85-100%
Immunity: No protective
antibody
response identified
Outcome Following Hepatitis C Infection
HCV - Diagnosis
1000
Acute HCV Infection
HCV RNA positive
800
Anti-HCV
600
ALT
(IU/L)
400
Symptoms
200
Normal
0 ALT
0 2 4 6 8 10 12 24 1 2 3 4 5 6 7
Weeks Months
Time After Exposure
Hoofnagle JH, Hepatology 1997; 26:15S
Hepatitis C: Typical Serologic Course
HCV
antibody
Symptoms
Person is sick,
but test for
Hep C is
Titer
negative
ALT
(liver
functio
n test)
Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after
Exposure
VIROLOGICAL TOOLS
Serological assays
Serological determination of the HCV genotype
The currently available assay (Murex HCV serotyping 1-6 HC02, Abbott
Laboratories, North Chicago, Illinois) identifies the type (1 to 6), but does
not discriminate among the subtypes, and provides interpretable results in
approximately 90% of chronically infected immunocompetent patients.
HCV RNA levels falling above the upper limit of quantification of the assay
are underestimated and the samples must be retested after 1/10 to 1/100
dilution in order to achieve accurate quantification.
The most promising approach for the future is fully automated real-time
PCR assays, which are faster, more sensitive than classical target
amplification techniques and are not prone to carryover contamination.
Assay Manufacturer Technique Lower limit of Dynamic range of
detection quantification
(qualitative (quantitative assay)
assay)
Amplicor® HCV v2.0 Roche Molecular Systems Manual RT-PCR 50 IU/ml NA
Amplicor HCV Monitor® Roche Molecular Systems Manual RT-PCR 600 IU/ml 600-500,000 IU/ml
v2.0
Cobas® Amplicor HCV Roche Molecular Systems Semi-automated RT-PCR 600 IU/ml 600-500,000 IU/ml
Monitor v2.0
RT : Abbott
LCx HCV RNA Quantitative
reverse transcriptaseSemi-automated RT-PCR
Diagnostic 25 IU/ml 25-2,630,000 IU/ml
Assay PCR : polymerase chain reaction
TMA
Versant® HCV RNA:3.0
transcription-mediated
Bayer HealthCare amplification
Semi-automated bDNA 615 IU/ml 615-7,700,000 IU/ml
Assay
bDNA : “branched DNA“
Cobas® TaqMan HCV Test NA : not
Roche applicable
Molecular Systems Semi-automated real-time 15 IU/ml 43-69,000,000 IU/ml
*for 0.2 ml or 0.5 ml of plasma analyzed,PCR respectively
Abbott RealTime Abbott Diagnostic Semi-automated real-time 30 IU/ml or 12 IU/ml* 12-100,000,000 IU/ml
PCR
• Most patients with chronic hepatitis C have levels of HCV RNA
(viral load) between 100,000 (105) and 10,000,000 (107) copies per
mL. Expressed as IU, these averages are 50,000 to 5 million IU.
• There are several definitions of a “low level” of HCV RNA, but the
usual definition is below 800,000 IU (~ 2 million copies) per mL.
VIROLOGICAL TOOLS
Molecular determination of the HCV genotype (genotyping)
Negative Positive
• Liver biopsy is also helpful in ruling out other causes of liver disease, such as
alcoholic liver injury or iron overload.
• This test also requires special handling of liver tissue and thus is not
appropriate fo routine clinical use.
Liver Biopsy
• HCV causes the following changes in liver tissue:
• Necrosis and inflammation around the portal areas, so-called "piecemeal necrosis" or
"interface hepatitis."
• Fibrosis, with early stages being confined to the portal tracts, intermediate stages
being expansion of the portal tracts and bridging between portal areas or to the central
area, and late stages being frank cirrhosis characterized by architectural disruption of
the liver with fibrosis and regeneration.
• Grading and staging of hepatitis by assigning scores for severity are helpful in
managing patients with chronic hepatitis.
• The degree of inflammation and necrosis can be assessed as none, minimal, mild,
moderate, or severe. The degree of fibrosis can be similarly assessed. Scoring
systems are particularly helpful in clinical studies on chronic hepatitis.
Histologic grading and staging in hepatitis C
Scale Necro- Fibrosis Total score
inflammation
Histology 0–18 0–4 0–22
Activity
Index
(HAI)12
Ishak 0–18 0–6 0–24
modified
HAI13
METAVIR14 0–3 0–4 0–7
Is liver biopsy mandatory in children with chronic
hepatitis C?
• On the basis of the studies available so far, chronic hepatitis C in children
seems to be a milder disease with a more favourable natural course when
compared to hepatitis C virus (HCV) infection in adults.
• Rheumatoid factor and low platelet and white blood cell counts are frequent in
patients with cirrhosis, providing clues to the presence of advanced disease.
• The enzymes lactate dehydrogenase and creatine kinase are usually normal.
• Albumin levels and prothrombin time are normal until late-stage disease.
DIAGNOSIS OF HCV INFECTION
Acute hepatitis C
• Patients with a suspicion of acute hepatitis C should be tested for both anti-
HCV antibodies by EIA and HCV RNA with a sensitive technique, i.e. an
HCV RNA assay with a lower limit of detection of 50 IU/ml or less
• Acutely infected patients can also have both HCV RNA and anti-HCV
antibodies at the time of diagnosis. It is difficult, in this case, to distinguish
acute hepatitis C from an acute exacerbation of chronic hepatitis C or an
acute hepatitis of another cause in a patient with chronic hepatitis C
DIAGNOSIS OF HCV INFECTION
Acute hepatitis C
• Acute hepatitis C is very unlikely if both anti-HCV antibodies and HCV RNA
are absent.
• Apart from such cases, the presence of anti-HCV antibodies in the absence of
HCV RNA is generally seen in patients who have recovered from a past HCV
infection.
• Indeed, neither anti-HCV antibodies nor the HCV RNA load correlate with
the severity of liver inflammation or fibrosis nor with their progression. Thus,
they cannot be used to predict the natural course of infection or the onset of
extrahepatic manifestations.
Differential Diagnosis
The major conditions that can be confused clinically with chronic
hepatitis C include
• autoimmune hepatitis
• chronic hepatitis B and D
• alcoholic hepatitis
• nonalcoholic steatohepatitis (fatty liver)
• sclerosing cholangitis
• Wilson disease
• alpha-1-antitrypsin-deficiency-related liver disease
• drug-induced liver disease
What is the most effective therapy
for hepatitis C?
• Combination therapy results in better treatment responses than monotherapy,
but the highest response rates have been achieved with pegylated interferon in
combination with ribavirin.
• Selected patients who fail to achieve an SVR may benefit from re-treatment
with pegylated interferon-based regimens.
• Test for HCV genotype (or serotype) to help determine the duration of
therapy and dose of ribavirin.
• Counsel the patient about the relative risks and benefits of treatment.
Side effects should be thoroughly discussed.
Which patients with hepatitis C should be treated?
• All patients with chronic hepatitis C are potential
candidates for antiviral therapy.
• Treatment is recommended for patients with an increased
risk of developing cirrhosis.
These patients are characterized by
• detectable HCV RNA levels higher than 50 IU/mL,
• a liver biopsy with portal or bridging fibrosis,
• and at least moderate inflammation and necrosis.
• The majority also have persistently elevated ALT values
Which patients with hepatitis C should b treated?
• All patients with chronic hepatitis C should be vaccinated against hepatitis A,
and seronegative persons with risk factors for hepatitis B virus (HBV) should
be vaccinated against hepatitis B.
• Although most of these patients have mild disease, histologically, some may
progress to advanced fibrosis and cirrhosis.
• No vaccine
• IG does not protect
Prognostic Tests
Prognostic Tests