1. Cengiz Pata Gastroenterology Department, Yeditepe University
Hepatitis C
Cengiz Pata
Gastroenterology Department, Yeditepe University
Now let us move on to talk about the epidemiology of hepatitis C.

2. Hepatitis C Virus Infection Magnitude of the Problem
Nearly 4 million persons in United States infected
Approximately 35,000 new cases yearly
85% of new cases become chronic
Leading cause of
Chronic liver disease
Cirrhosis
Liver cancer
Liver transplantation
Nearly 4 million persons in the United States are infected with hepatitis C virus (HCV). Approximately 35,000 new cases are diagnosed each year. A major issue is that most cases—approximately 85%—become chronic resulting in hepatitis C accounting for the leading cause of chronic liver disease, cirrhosis, and liver cancer in the United States, as well as the number one indication for liver transplantation.
Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

3. Hepatitis C Virus Fate of Acute Infection
Spontaneous
resolution
15%
As previously mentioned, the majority of individuals exposed to HCV will develop chronic infection; however, 15% of patients exposed to HCV are somehow capable of spontaneously resolving this infection. Research is currently ongoing to better understand how these people can resolve their infection, and this may shed some light on how to better treat hepatitis C in the future.
Chronic
85%
Alter MJ, et al. N Eng J Med. 1999;341:

4. Hepatitis C Virus Response to Acute Infection
200
HCV RNA
+/- + -
150
Resolution
ALT (IU/l)
100
Chronic
This next slide looks at the biochemical and virologic response of patients exposed to HCV. In the green line you can see acute elevation in liver transaminases within the first couple of weeks after exposure to the virus, indicating acute HCV infection. Notice in the red bar I have indicated presence or absence of HCV RNA. During the acute phase of HCV infection, if you test for HCV, sometimes the virus will be detectable, but at other times the virus is undetectable. Because of this intermittent viremia, virologic assays are not the best assays to screen for acute hepatitis C.
Over the next couple of weeks of infection, liver transaminases decline and then go into an undulating pattern over the next years, when the serum alanine aminotransferase (ALT) can fall into the normal range for either brief or prolonged periods of time, only to elevate again. This shows that individuals with chronic hepatitis C can have both elevated liver enzymes and normal liver enzymes, and sometimes they can have persistently normal liver enzymes for long periods of time. However, these individuals will test positive for antibodies to hepatitis C and, if they have chronic infection, will be viremic.
The blue line indicates an individual who had spontaneous resolution from hepatitis C. Again, you see acute elevation of liver transaminases during the acute phase, intermittent viremia in the first couple of weeks after the infection, and then the liver transaminases coming down and remaining persistently normal. It is important to recognize that individuals who have been exposed to HCV but develop spontaneous resolution will also develop antibodies to hepatitis C. This is the type of individual who may go and donate blood to a blood bank and have a positive antibody for hepatitis C or be noted as having a positive antibody on life or health insurance physical exams. However, they have persistently normal liver enzymes, and when tested for HCV RNA, they are virus undetectable. 50 6 12 18 24
Month
Illustration by Mitchell L. Shiffman, MD.

5. Hepatitis C Virus Infection Natural History
Acute HCV
Resolved
15% (15%)
Chronic HCV
85% (85%)
Stable
80% (68%)
Cirrhosis
20% (17%)
The next slide illustrates the natural history of HCV infection. As previously mentioned, a small percentage of individuals will go on to spontaneous resolution—about 15%—whereas 85% develop chronic disease. Of this 85% who develop chronic disease, about 80%, (68% of all infected individuals), will have stable chronic hepatitis without significant progression over the next 20 years. By contrast, 20% of those who develop chronic disease (17% of all infected individuals) will develop cirrhosis over the next years. Of these cirrhotic patients, many will continue to progress slowly, and about 25% will rapidly develop hepatocellular carcinoma (HCC) or liver failure. Thus, liver cancer and liver failure occur in approximately 4% of patients who are exposed to HCV over a 20- to 25-year period.
Slowly
progressive
75% (13%)
HCC
Liver failure
25% (4%)
HCC, hepatocellular carcinoma

6. Hepatitis C Virus Infection Population at Risk
Transfusion of blood products before 1992
Intravenous drug use
Nasal inhalation of cocaine
Chronic renal failure on dialysis
Incarceration
Occupational exposure to blood products
Transplantation of an organ/tissue graft from an HCV-positive donor
Body piercing and potentially tattoo
Who are the patients at risk to develop chronic HCV infection and develop this progressive liver disease? They are individuals who were exposed to blood products before the development of hepatitis C testing, individuals who intermittently used or continual to use intravenous drugs or inhale cocaine, and individuals with chronic renal failure on dialysis. These individuals have a high risk of HCV exposure either through blood products used to treat the complications of chronic renal failure or because of contamination in dialysis units. Incarcerated individuals, many of whom have used drugs in the past, have a high prevalence for HCV infection. Occupational exposure to blood products is a potential mode of exposure, and individuals who receive organ or tissue grafts from HCV-positive donors through transplant are also exposed to the virus. Finally, individuals who have participated in body piercing and tattooing may be exposed through these activities.
Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

7. Hepatitis C Virus Infection Prevalence
4.0
3.0
Anti-HCV Positive (%)
2.0
1.8%
1.0
The next slide looks at the prevalence of hepatitis C antibodies in patients in the United States broken down by race and sex. Overall, 1.8% of the US population has antibodies to hepatitis C. In blacks, the prevalence exceeds 3.5%, and is approximately twice as high as in whites. Hepatitis C antibodies are also twice more common in males than in females.
All W B H M F
Sex
Race
B, Blacks; F, female; H, Hispanic; M, male; W, Whites.
Alter MJ, et al. N Eng J Med. 1999;341:

8. Hepatitis C Virus Infection Prevalence by Age
5.0
4.0
3.0
Anti-HCV Positive (%)
2.0
This next slide looks at the age distribution of patients with hepatitis C. You can see that the peak age for HCV infection is years. Prevalence is very low in children younger than 11 years and in individuals older than 70 years of age. In the United States, the prevalence among 30 to 49 year olds is anywhere from 3.5% to 4.0%. If these individuals are not identified and treated, they will continue to progress as they get older, developing more severe liver disease and flooding our hospitals with end-stage liver disease. For example, the patients that currently represent the most common indication for liver transplantation—end-stage hepatitis C—are between 50 and 69 years of age. If the 30- to 49-year-old patients, who have a much higher prevalence of infection, are not identified and treated now, they will develop more progressive liver disease over the next years and many will require liver transplantation. In this scenario, this group of individuals will completely outstrip our ability to care for them. Therefore, it is estimated that the risk of death from hepatitis C in the future will increase dramatically.
1.0
< 11
11-19
20-29
30-39
40-49
50-59
60-69
≥ 70
Age Group
Alter MJ, et al. N Eng J Med. 1999;341:

9. Hepatitis C: Diagnosis and Management
Now let us move on to our next section on diagnosis and management.

10. Management of Chronic HCV Tests Utilized
Disease Severity
Response to Therapy
AST/ALT
Bilirubin
Albumin
Pro-time (INR)
Platelet count
Liver histology
ALT
HCV RNA
HCV genotype
LFTs
This first slide looks at the tests that are used to identify patients with hepatitis C and assess disease severity and response to therapy. The first, aspartate aminotransferase and ALT tests, are not really liver function tests although many physicians refer to them as such. Rather, they measure liver transaminases, which are indicative of inflammation or irritation to the liver. The true tests to measure liver function include bilirubin, albumin, and prothrombin time or international normalized ratio. When the liver has dysfunction, these tests start to show abnormalities. Unfortunately, that does not occur until patients develop cirrhosis. Therefore, the majority of patients with chronic hepatitis C show normal liver function based upon these liver function tests.
One of the most sensitive tests of advanced liver disease is the platelet count. A large number of studies have now demonstrated that thrombocytopenia—platelet counts below the lower limit of normal—is indicative of cirrhosis in individuals who do not have some sort of primary platelet or bone marrow disorder. Identifying thrombocytopenia is an easy way to identify patients with cirrhosis, and clearly liver histology represents the gold standard of determining the severity of disease and histologically can identify cirrhosis and the degree of scarring or fibrosis is present in the liver.
One test we monitor to determine treatment response is serum ALT. If treatment is working effectively, we expect that the ALT levels will drop back down into the normal range on therapy. We also monitor the level of HCV RNA, and the goal is to have virus levels become undetectable during treatment. Hepatitis C virus genotype determines how long we need to treat patients, and liver histology can be used as a marker to show that the liver has improved after therapy.

11. Viral Hepatitis Role of Diagnostic Testing
Identify patients with viral hepatitis infection
Previous exposure to hepatitis virus
Active infection
Inactive infection
Resolved infection
Assess response to therapy
Prior to onset of treatment
During and following treatment
It is critical when evaluating patients with hepatitis C to measure HCV RNA levels. The roles of diagnostic testing are to identify patients with viral hepatitis infection, to measure previous exposure to the HCV, to differentiate active from inactive infection and resolved infection, and to assess response to therapy both during and after treatment.

12. Hepatitis C Virus Host Production of HCV Antibodies
HCV infects cell
HCV proteins expressed on surface of hepatocytes
Antibodies to HCV proteins produced by host
HCV antibodies DO NOT convey immunity
This slide illustrates the basis of antibody production in an individual after exposure to HCV. As you can see, the schematic illustrates the virus infecting the liver cell. The virus then produces large quantities of its own proteins or antigens, which are then expressed on the cell surface of the infected hepatocyte. The immune system recognizes this expression and reacts by producing antibodies, which then bind to the infected cell. That is one way in which the immune system attempts to rid the system of infected cells. However, as we know, this is not very successful without treatment.
It is important to recognize that the hepatitis C antibodies circulating in response to this process are not protective antibodies. Instead, they are simply markers of previous exposure. If an individual is hepatitis C antibody positive but virus negative, and then participates in risky behaviors, he or she still has the potential to become infected with hepatitis C. Y Y Y Y Y Y Y Y
Illustration by Mitchell L. Shiffman, MD.

13. HCV Antibody Testing Limitations
False positives
Autoimmune disorders
Spontaneous resolution of viral infection
False negatives
Chronically immune suppressed
Transplant recipients
Chronic renal failure on dialysis
HIV positive
As stated, the primary limitation of antibody testing is the potential for false positives. False positives can occur in individuals with high levels of circulating autoantibodies, particularly those individuals with autoimmune disorders or individuals who were previously exposed to HCV but had spontaneous resolution. These individuals will continue to have circulating antibodies and a positive anti-HCV test but negative HCV RNA tests.
It is important to recognize that the ELISA anti-HCV screening test does not accurately detect HCV in certain populations, such as patients in whom the antibodies are poorly produced. False negatives occur in chronically immunosuppressed individuals, including transplant recipients, chronic renal failure patients on dialysis, or HIV-positive patients.

14. Hepatitis C Virus Genotypes in the USA
17%
Type 3
There are 3 major types of HCV in the United States. The most common is genotype 1, which represents approximately 72% of HCV-infected patients in the United States. The prevalence of genotypes 2 and 3 is fairly equally split and represents the majority of the remaining approximate 25%. In this large study published in 2004, genotype 2 represented 17% and genotype 3 represented 10% of HCV-infected patients in the United States. There are other HCV genotypes, including genotypes 4, 5, and 6, which are almost exclusively found in individuals originating from areas of the world where these particular genotypes are endemic. For example, genotype 4 is almost completely restricted to individuals who immigrate to the United States from Egypt and the Middle East, genotype 5 is predominantly from South Africa, and genotype 6 is generally from Southeast Asia.
10%
Type 1
72%
All others 1%
McHutchinson JG, et al. N Engl J Med. 1998;339:

15. Hepatitis C Virus Infection Liver Biopsy
Only test that can accurately assess
Severity of inflammation
Degree of fibrosis
Determines the following
Risk for developing cirrhosis in future
Need for therapy
Need for ongoing therapy when initial treatment has failed
The final way to assess liver disease severity in hepatitis C is with liver biopsy. This is the only test able to accurately assess severity of inflammation and degree of fibrosis. The baseline degree of inflammation and fibrosis are able to determine risk of cirrhosis development in the future, the need for therapy, and the need for ongoing therapy if initial treatment has failed. For example, an individual who failed interferon therapy and has mild liver disease and no apparent cirrhosis based on liver biopsy, has little urgency to undergo retreatment with new or more aggressive therapies. In contrast, an individual with more scarring and bridging fibrosis on biopsy may request such treatments. The biopsy is very useful for managing patients in these scenarios.

16. Assessment of Liver Histology Noninvasive Serum Tests
1.0
1.0
0.8
0.8
0.6
0.6
FIBROTEST
ACTITEST
0.4
0.4
0.2
0.2
Recently we have heard about some noninvasive tests that may replace liver biopsy. These tests are helpful sometimes, but not always. These data were presented several years ago for one of these noninvasive tests, the FibroTest. This figure shows the stage of fibrosis according to liver biopsy vs stage according to FibroTest. In individuals without scarring (stage 0 fibrosis) fibrosis, their FibroTest results fall into a wide range, such that a result of 0.3 could represent mild fibrosis or no fibrosis. Of more importance, higher levels on the FibroTest—between 0.50 and 0.75—do not differentiate individuals with moderate or severe fibrosis from patients with cirrhosis.
In my own practice, I do not find the noninvasive serum markers of fibrosis very helpful because there is too much overlap in these tests. For patients who cannot make a decision regarding course of treatment, the FibroTest often will not help to answer that question. For these patients, a liver biopsy is necessary. 1 2 3 4 1 2 3
Fibrosis Stage
Activity Grade
Poynard T, et al. Hepatology. 2003;38:

17. Chronic HCV With Normal Serum ALT ALT Patterns and Flares
120
Single elevations
100
Periodic elevations
Always normal 80
ALT (IU/l) 60
ULN 40
Let us look at a particular group of patients with hepatitis C—those with persistently normal serum ALT. Persistently normal serum ALT used to be thought of as an indicator of mild disease and no liver damage. That may not be the case. As shown in this slide, patients with persistently normal ALT can fall into 3 different patterns: 1) the group that is always normal, 2) the group that has the single spikes of elevations in serum ALT, and 3) the group that temporarily becomes abnormal and then drops down into the normal range. It is fairly obvious from this graph that it could be easy to miss individuals with single elevations or prolonged elevations if serum ALT is not tested frequently enough. In general, the more you test a patient with a normal ALT, the more you will find that it is not normal all the time. 20 3 6 9 12 15 18 21 24
Month
Illustration by Mitchell L. Shiffman, MD.

18. Chronic HCV Infection Symptoms
Symptomatic
100
37%
Cirrhosis 80 7% 60
Percentage of Patients 40
If you ask patients with hepatitis C how they feel, about 56% of them say they are asymptomatic, about 37% say they have symptoms, and about 7% have complications of cirrhosis. Of those who have symptoms, the most common symptom is simply fatigue—80% of symptomatic patients complain of fatigue. The symptoms can be very, very subtle indeed. 20
56%
Asymptomatic
Fatigue
Unpublished data from MCV Hepatitis Program, 1995.

19. Chronic HCV Infection Progression to Cirrhosis
Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis
Approximate Percentage of
Patients With Cirrhosis
100 80
Bridging 60
Portal
What happens to these minimally symptomatic individuals as we follow them over time? The majority of individuals will develop progressive fibrosis and eventually cirrhosis from hepatitis C. The liver biopsy helps predict the risk of developing cirrhosis over a 20-year period in patients with hepatitis C. For individuals who do not have any evidence of fibrosis on their initial biopsy, the risk of developing cirrhosis over the next 20 years is only about 25% to 30%. On the other hand, once a patient has fibrosis, he or she will develop progressive fibrosis and eventually cirrhosis, it will just take time. According to this study, 100% of individuals with portal fibrosis develop cirrhosis, but it takes years. However, individuals with high levels of fibrosis on initial biopsy will develop cirrhosis sooner, in only about 8-10 years. That initial biopsy can be very helpful in providing feedback to the patient on why they should embark on therapy even though they are asymptomatic or minimally symptomatic. 40
None 20 5 10 15 20
Time (Years)
Yano M, et al. Hepatology. 1996;23:

20. Hepatitis C Virus Infection Identification of Patients
Found to have elevated serum ALT during
Routine physical examination
Routine blood testing after starting certain medications
Test positive for anti-HCV during
Volunteer blood donation
Health or life insurance applications
Physician
Inquires about previous risk behaviors
How do we identify patients with hepatitis C? There are a couple of ways. First, we find patients with elevated serum liver transaminases either during routine physical examination or routine blood testing after starting certain medications. Patients may also test positive for anti-HCV during volunteer blood donations or for life or health insurance physicals. However, one of the most important ways that physicians can identify patients with hepatitis C is to inquire about previous risk behaviors and screen patients who disclose these behaviors.

21. Hepatitis C: Extrahepatic Manifestations
The final part of this program deals with another way that individuals with hepatitis C come to medical attention—through extrahepatic manifestations of the disease.

22. Chronic Hepatitis C Virus Extrahepatic Manifestations
Nonspecific antibodies
Essential mixed cryoglobulinemia
Glomerulonephritis
Porphyria cutanea tarda
Leukocytoclastic vasculitis
Mooren’s corneal ulcer
Non-Hodgkin’s lymphoma
Autoimmune thyroiditis
Diabetes mellitus
Sjögren’s syndrome
Hepatitis C is associated with many extrahepatic manifestations, including nonspecific antibody production, essential mixed cryoglobulinemia, glomerular nephritis, porphyria cutanea tarda (PCT), leukoclastic vasculitis, non-Hodgkin’s lymphoma, autoimmune thyroiditis, diabetes, and Sjögren’s syndrome.

23. Chronic Hepatitis C Virus Autoantibodies
HCV, %
Control, %
Rheumatoid factor 70 8
Cryoglobulins 36
< 1
ANA
> 1:40
> 1:180 21 13 10 2
Antismooth muscle 7
Anti–liver-kidney microsome 5
Antithyroid
Many individuals with hepatitis C have circulating autoantibodies and are sometimes incorrectly diagnosed with other disorders. For example, 70% of patients with hepatitis C have circulating rheumatoid factor. Approximately one third have cryoglobulins, and anywhere from 13% to 21% have low-titer or high-titer antinuclear antibodies (ANA). A slightly lower percentage have smooth muscle antibodies—about 5% have antibodies to liver or kidney microsomes—and about 7% have antithyroid antibodies. These antibodies are all significantly higher than we see in the control population without hepatitis C.
Pawlotsky JM, et al. Hepatology. 1994;19:

24. Cryoglobulinemia Classification
Immunoglobulin
Classification I
Monoclonal
No rheumatoid factor
Primary II
Polyclonal IgG
Monoclonal IgM
Rheumatoid factor
Secondary mixed
HCV infection
III
Polyclonal IgM
Infections
Autoimmune disorders
Lymphoproliferative diseases
Cryoglobulinemia is classified into 3 types. Type 2 cryoglobulinemia is found almost exclusively in individuals with hepatitis C and is associated with polyclonal IgG, monoclonal IgM, and rheumatoid factor.
Cacoub P, et al. Curr Opin Rheumatol. 2002;14:29-35.

25. Immune Manifestations of HCV Pathogenesis
Why do individuals with hepatitis C develop so many autoantibodies? The schematic in this slide illustrates one of the proposed mechanisms. Because hepatitis C is a rapidly reproducing virus that is constantly changing because of the high mutation frequency, it is able to evade the immune response. Because the immune system wants to constantly attack this virus, there is a constant immune stimulation, causing clonal expansion of B cells. Under genetic and environmental factors which are poorly defined, the immune system produces polyclonal IgG, monoclonal IgM, and rheumatoid factor. These antibodies bind to HCV causing large aggregates called cryoglobulins, which trap hepatitis C in dependent areas and blood vessels causing the symptoms of cryoglobulinemia.
Illustration by Mitchell L. Shiffman, MD

26. HCV and Cryoglobulinemia Dermatitis
Occurs in dependent areas
Deposition of cryoglobulins in small capillaries
Ulcerations may develop
Pruritic
This slide illustrates the dermatitis of cryoglobulinemia—a patchy discoloration in the lower extremities resulting from deposition of cryoglobulins in small capillaries. Ulcerations may develop, and these areas can be very pruritic.

27. HCV and Cryoglobulinemia Manifestations
Dermatitis (dependent areas)
Vasculitis
Myalgias (fibromyalgia?)
Arthralgias (RA and/or ANA positive)
Membranoproliferative glomerulonephritis
Neuropathy
Chronic fatigue syndrome (?)
Cryoglobulinemia can cause several manifestations. In addition to the dermatitis, it can also cause vasculitis and myalgias. Clearly some fibromyalgia patients have myalgias from hepatitis C and cryoglobulinemia. Cryoglobulinemia can also cause arthralgias. Many of these patients are rheumatoid factor and/or ANA positive. Cryoglobulinemia can also cause membranal proliferative glomerular nephritis, neuropathy, and in some cases, chronic fatigue syndrome.

28. Hepatitis C: Treatment
In the final portion of this program we will discuss the treatment of hepatitis C. Why is it so important to have covered so much information on recognizing hepatitis C and detailing how hepatitis C progresses, causes cirrhosis, and causes liver cancer? It is important because there are highly effective treatments for hepatitis C.

29. Treatment of Chronic HCV Peginterferon and Ribavirin
100 80 60
Sustained Virologic
Response (%)
PegIFN-2a/RBV 40
PegIFN-2b/RBV
The 2 studies shown in this slide illustrate the effectiveness of the 2 peginterferons approved for treatment of hepatitis C—peginterferon alfa-2a and peginterferon alfa-2b. Approximately 80% of individuals with genotype 2 or 3 HCV achieve a sustained virologic response with peginterferon combined with ribavirin, meaning 80% are cured of hepatitis C. Unfortunately, genotype 1 is more resistant to treatment, yet 40% to 45% of patients with genotype 1 achieve a sustained virologic response after treatment with peginterferon and ribavirin. 20 1
2-3
Genotype
Fried MW, et al. N Eng J Med. 2002;347: Manns MP, et al. Lancet 2001;358:

30. Treatment of Chronic HCV Effect on Development of HCC
Interferon treatment reduces the risk of developing hepatocellular carcinoma among patients with chronic HCV (P = .002)
Hepatocellular carcinoma incidence
Untreated controls: 38% (24%-58%)
Interferon-treated patients: 4% (1%-15%)
HCC risk ratio: ( ; P = .01)
If you examine patients with cirrhosis who achieve a sustained virologic response after interferon therapy, the risk of developing liver cancer is significantly reduced. Compared with untreated controls where the risk of developing cancer was 38% over long-term follow-up, the risk was reduced to 4% in patients treated with interferon, a highly significant risk reduction.
Nishiguchi S, et al. Lancet. 1995;346: