This lecture is about Spectrum of HCV infection presented by Dr. Muhammad Mostafa Abdel Ghaffar, Head of Tropical Medicine Department, Ahmed Maher Teaching Hospital. The lecture was presented in the scientific meeting of Internal and Tropical Medicine departments, Ahmed Maher Teaching Hospital titled (Towards Eradication of HCV in Egypt) in celebration of World Hepatitis Day on July 28, 2016. https://www.facebook.com/AMTH.IM https://www.facebook.com/events/1072758396145209/ http://www.no4c.com

1. Muhammad Mostafa, MD

2. The spectrum of HCV infection is a quite
changeable demonstration
It starts by acquiring the infection but
thereafter and for many reasons it is difficult
to predict the outcome…..

4. Acute
hepatitis
Chronic
hepatitis
Liver cirrhosis
End stage liver
disease
Hepatocellular
carcinoma
Extra-hepatic
manifestations

5. In developed countries:
The incidence of acute infection has
decreased
◦ Blood products are screened
◦ Universal precautions for infection control
◦ Mass education on risk and transmission
The burden of advanced disease has
increasesd

6. HCV can be transmitted via these routes:
 Parenteral (blood contaminated instruments,
blood or blood products transfusion, and
intravenous drug use)
 perinatal transmission (rate: 4-10%)
 Occupational exposure
 Sexual transmission

8.  Incubation period ranges from 2-12 weeks
 Clinically silent for most infected people
 Jaundice in 15% of patients
 20%-35% of patients will spontaneously clear the virus
 Younger women, icteric patients, low viral inoculum and
single nuleotide polymorphism near IL28B` gene increase
the likelihood of clearing infection

9.  HCV RNA becomes positive within 2 weeks of
exposure
 Most patients are Anti HCV positive within 8-12
weeks of exposure
 Positive HCV PCR and negative Anti HCV define acute
hepatitis C
 Seroconversion is a strong diagnostic tool of acute
HCV infection
 Transient viral clearance is possible during the course
of acute infection and PCR retesting is important

10.  If spontaneous clearance occurs, it typically happens
within 6 months, with a median time of clearance of
16 weeks
 Anti-viral treatment should be initiated if no
convalescence (HCV PCR still positive) occurs 3-4
months after onset of the disease specially in
asymptomatic patients
 Acute HCV infection is more responsive to treatment
than chronic and SVR is high even before the era of
DAD

12.  Chronic hepatitis C is defined as the persistence
of HCV RNA for 6 months or longer
 Most patients are asymptomatic but the most
common and least specific is fatigue
 Serum transaminases fluctuate over time and
most have levels 1.5-3 times the upper limit of
normal, rarely > 10 folds elevated
 Up to one third of patients have persistently
normal ALT activity

13.  No definite relation between transaminases
and inflammation or fibrosis on liver biopsy
 AST:ALT ratio of >1 correlate with histologic
cirrhosis
 5-25% develop cirrhosis within 20 years
 Adequate liver biopsy remains the gold
standard for evaluation of fibrosis and
inflammation. Other pathologic findings can
be also diagnosed

14.  Non invasive tools are used to evaluate
chronic hepatitis patients; APRI score,
fibrotest, transient elastography and
magnetic resonance elastography (MRE).

15.  Positive test is a marker of past or current
infection
 Anti-HCV antibody assay evolved for the first
time in 1988
 Anti-HCV IgM is of no importance and present in
approximately 50%% of chronic hepatitis C
 In 1990 first generation ELISA was licensed. The
reliance on only one target antigen produced
false positive and false negative results.

16.  Subsequent generations incorporated many
antigens from different regions of HCV genome
 EIA remains the best screening test for HCV
diagnosis (specificity >99%)
 False negative results occur in
immunosuppressed, hemodialysis patients and
patients with agammaglobulinemia.
 RIBA may be confirmatory when signal-to-cutoff
<4 by EIA

17.  Relies on detection of either signal
amplification or target amplification
 HCV RNA level has no prognostic value
 Different techniques are used with variable
lower limit of detection (LLD) and lower limit
of quantification (LLQ)
 Branched DNA method for signal
amplification is inadequate (LLQ 615 IU/ml)

18.  The most frequently used commercial assays
for target amplification are transcription
mediated amplification (TMA) and reverse
transcription polymerase chain reaction (RT-
PCR)
 HCV genotype is recommended for defining
the anti-viral treatment duration and will
become more important with direct-acting
anti-viral treatment
 Line probe hybridization assays (LiPA) are the
most widely used for genotyping

19. • Acute
HCV
• Chronic
HCV
hepatitis
•compensated
•decompensated
cirrhosis HCC

20. The outcome of HCV infection is governed by
the relation of the host, virus, environment
and the availability and efficiency of
diagnostic and therapeutic modalities.

21. Host factors:
 Age when infected
 Sex
 race
 Immune status
 Genetics predisposition
 Obesity and DM
 Smoking
 Heavy alcohol consumption
 Associated liver diseases (shistosomiasis,
fatty liver, HBV infection, HIV infection…)
 Liver iron accumulation

22. Viral factors:
 Ability to evade host immunity (viral
mutation, quasispecies generation,
interference with interferon signaling
pathway, infection of immune cells, down-
regulation of NK cell activity….)
 Viral factors such as genotype, quasispecies
and viral load are not consistently linked to
the outcome

24.  In the absence of therapy 20% of chronic HCV
patients will develop cirrhosis after an
average of 20 years
 The development of cirrhosis is often
clinically silent
 In cirrhotic patients, the annual rate of
decompensation is 2-5%

25.  Careful clinical examination and laboratory evaluation
may be helpful to detect early liver cirrhosis
 Liver pathology staging is the gold standard for the
diagnosis of liver cirrhosis
 Ultrasonography is not reliable for the diagnosis of
liver cirrhosis
 Transient elastography (fibroscan) is a non invasive
tool for the diagnosis of liver cirrhosis
 Combination of seromarkers are used to predict liver
fibrosis

26.  Liver cell failure and portal hypertension are
the end result of liver cirrhosis
 Portal hypertension can occur in cirrhotic
patients with normal liver functions
 Ascites, coagulopathy, jaundice and
enchephalopathy point to decompensated
liver disease

28.  Unlike HBV, hepatocellular carcinoma develop in
patients with HCV related liver cirrhosis
 Patients may be asymptomatic and discovered by
ultrasonography
 Ultrasonography and alpha fetoprotein every 6
months are used for HCC surveillance
 α fetoproein is a poor screening test for the
detection of HCC in the setting of chronic HCV
(sensitivity 60%) but level >200ng/ml in the
setting of liver mass has 90% sensitivity
 Surveillance ultrasonography every 3 months is
recommended in patients with lesions < 1cm

29.  CT scan and MRI either alone or combined are
used for the diagnosis of larger lesions and
to determine the extent of the disease
 Other seromarkers like des gamma carboxy
prothrombin (DCP), glycosylated α-
fetoprotein, α L fucosidase and glypican 3 are
evaluated for HCC screening
 Although debatable, the role of liver biopsy
in the diagnosis of HCC is still existing with
the risk of tumour seeding

30. Markers
The expression in the
serum/tissues of HCC Sensitivity (%) Specificity (%) Application
AFP Upregulation 41.0–65.0 80.0–94.0 Early diagnosis
AFP-L3 Upregulation 96.9 92.0 Early diagnosis
HSP70 Upregulation 57.5 85.0 Prognosis
GPC3 Upregulation 77.0 96.0 Diagnosis
SCCA Upregulation 84.0 46.0 Early diagnosis
GP73 Upregulation 76.9 - Diagnosis
FC-GP73 Upregulation 90.0 100.0 Diagnosis
GGT Upregulation 43.8 - Diagnosis
AFU Upregulation 90.0 97.5 Diagnosis
AFU+AFP Upregulation 95.0 100.0 Diagnosis
TGF-β1 Upregulation 89.5 94.0 Prognosis
VEGF Upregulation - - Recurrence and prognosis
AFP-mRNA Upregulation - - Recurrence and prognosis
miR-21 Upregulation 87.3 92 Diagnosis
miR-500 Downregulation - - Prognosis
miR-29 Downregulation - - Prognosis
miR-122 Downregulation - - Prognosis

31.  The evolving therapeutic modalities in the
treatment of HCC may carry a better outcome
for one of the leading causes of mortality in
HCV patients

33.  HCV infection is primarily a liver disease but
sometimes it is a real systemic disease
 HCV is not only a hepatotropic virus but also
a lymphotropic virus
 Type II or III cryoglobulinemia are found in up
to 50% of HCV patients but lead to clinical
manifestations in 30% of them
 B cell lymphoma is the most prevalent HCV
lymphproliferative disorder

34. Cryoglobulinemia
B cell lymphoma
AI thyroidits
AI hemolytic anemia
IR and DM
throboctopenia
PCT
Lichen planus
Myocarditis
Cardiomyopathy
Idiopathic pulm fibrosis
Glomerulonephrirtis
Peripheral neuropathy

35.  Extrahepatic manifestations should be
searched for in patients with hepatitis C as
they can be unmasked or aggravated during
the course of the disease or at the beginning
of antiviral treatment especially when using
immune-modulating drugs
 Early treatment of some extra-hepatic
diseases may be wise to avoid the relative or
absolute contraindication of antiviral drugs or
immune-modulating drugs at a later stage of
liver disease

36.  Spectrum of hepatitis C infection is dynamic
and variable
 Extra-hepatic manifestation of hepatitis C
and co-morbidities throughout a long natural
history create a major challenge

37.  The emergence of diagnostic tools and
therapeutic modalities will certainly have a
robust effect on the spectrum of hepatitis C
 HCV is curable and we may no longer see this
spectrum