Corinne Borel CNA   

Disease:

Hepatitis (def) C a form of Viral Hepatitis (def)

Causitive Agents

There are a variety of non-viral as well as viral diseases which can cause Hepatitis.  Viral Hepatitis has 5 typical forms which have been identified as: Hepatitis: A, B, C, D, E.  as well as adenovirus (def), parvovirus (def), herpes virus (def), cytomegalovirus (def) and Epstein-Barr (def).    The emphasis here will be on Hepatitis C because of its particular relevance in the US for chronic liver disease (def) and liver failure (detailed uner “Epidemiology”).

Hepatitis C (HCV) is a single strand, RNA virus which is enveloped, and 50nm in diameter.  The virion is round with a polyhedral capsid.  HCV is the only viral hepatitis belonging to the Flaviviridae virus family which ranges in size from 45-60 nanometers (def) and includes Dengue Fever (def) and West Nile Virus (def).   Flaviviridae viruses are common in human populations as well as various other animal populations such as canines (def) and equines (def).   HCV, though, only infects humans.

Noteworthy for the future development of a vaccine is that there are ½ dozen genotypes, with subtypes numbered at over 50.  Subtypes can vary by 1/5th  of their sequence while genotypes can vary by roughly 1/3 of the sequence of their nucleotides.  This variability, the mutation rate,  along with the host’s low T-lymphocyte response makes this virus difficult to prevent and treat.  Nearly ¾ of the Hepatitis C infections in the U.S. are caused by what is referred to as Genotype 1.  There is a Genotype 1a and 1b, neither responding well to treatment.

Epidemiology

Hepatitis C was only recognized as a distinct class of viral hepatitis as recently as 1988.  Initially, in 1974,  it was described as non-A, non-B Hepatitis. By 1989 HCV was recognized as the main cause of Hepatitis in the United States for those with neither Hepatitis A nor Hepatitis B.  A Consensus Development Conference was held by the National Institutes of Health in 1997.  It was recognized that the recent and slow recognition by health professionals of this distinct type of Hepatitis was hampering public health efforts.  By the next Consensus conference in 2002 a significant increase in HCV rates since1997 was recognized.  Now in 2010 the Institutes of Medicine issued a Call to Action, noting the need for a more concerted public health response.

In the 1980’s 180,000 to 291,000 total new infections of HCV per year were estimated meaning that now 20-30 years later there is an expected spike of cirrhosis and liver cancer cases associated with those infections which have became chronic.

Populations most at risk (rate of 70%-90%) are IV drug users and hemophiliacs(def) receiving blood transfusions before 1992.  After 1992 blood screening mechanisms were put in place which successfully lowered transmissions from blood transfusions in medical settings. People on hemodialysis are also a high risk group requiring periodic testing.  Populations in prison and homeless also have a disproportionately high rate (15-20%).  Having multiple sexual partners has been determined as a risk factor, categorizing Hepatitis C as a sexually transmissible disease even though this is not considered the primary means of transmission.  Monogamous couples where one partner is infected have an extremely low transmission rate. 

Hepatitis C is significant because it is the primary cause of chronic liver disease in the United States.  Noteworthy is that there are more people in the U.S. with both Hepatitis C (approximately 4 million) and Hepatitis B combined: 5.3 million or 2% of the U.S. population; than there are infected with HIV/AIDS, though much less attention has been paid to this silent killer.  This HCV induced liver disease is the chief cause of liver cancer and need for liver transplant in the United States with a yearly
                                                                                                                                               
Hepatocellular carcinoma(HCC)(def) contraction rate of up to 4%.  Furthermore, a number of diseases are associated with having Hepatitis C.  A key problem in containing this illness is that it is asymptomatic for most until there are symptoms of liver damage, in advanced stages.  There is an acute infection (def) which may produce signs and symptoms, but for most it progresses to be a chronic asymptomatic infection making detection and tracking very difficult.  For this reason there is a large gap between reported cases and estimated cases.

Only 14 states in the U.S. give full risk factor details in reporting of the acute illness (which is only a small segment of those infected).  A dozen states provide none of this epidemiological information with the rest of US states reporting some data.  Correcting the spotty risk factor reporting procedures would greatly help in future tracking and management of HCV. 

There are notable geographic clusters of the illness.  Vermont and Oklahoma had the highest reported incidence of acute HCV reported in 2007, both at 1.4 per 100,000.  Next, per 100,000,were New Jersey  (one of the states which in 2007 provided no data on risk factors for those reported with acute illness) at 1.1;  West Virginia 1.0; Michigan at 0.9; Rhode Island 0.8; Kentucky 0.7 and both Tennessee and Connecticut at 0.6.  Most other states had incidences of 0.1-0.5.  Noteworthy in these numbers for 2007 is that a full dozen states had no cases reported.  It appears there is a cluster in the New England area and New Jersey, poorer southern states such as West Virginia, Kentucky and Tennessee.  Oklahoma has a Native American population which may be raising the incidence levels.

Currently, the ethnic/racial groups with highest incidence are Native American/Alaskan natives and non-Hispanic Whites, though historically African Americans have had a higher incidence than non-hispanic Whites.  African American males are most likely to not clear the virus and develop chronic liver disease.  African American males also have the poorest physical response to treatment, with only 30% responding to even extended treatment regimens.   In general, there is both a higher incidence and poorer disease outcomes for males of all groups and those who are older.  Children born with the illness and young females tracked 20-30 years later have much more favorable outcomes in terms of lack of fibrosis and cirrhosis.

It has been recognized that one of the reasons the disease is not being more aggressively screened for and prevented is that health professionals have not been sufficiently informed or proactive in screening, hence the above cited “Call to Action”. 

Transmission

Hepatitis C is a blood-borne pathogen and can be transmitted by direct contact with blood as well sexually or through childbirth.  Intranasal cocaine use may possibly be a transmission mode as well.  Prior to July 1992 it was possible to receive Hepatitis C from blood transfusions (def) or organ transplants and prior to 1987 it was possible to become infected by clotting factors (def).  IV drug users, those who have many sexual partners, those requiring dialysis (def) are at risk for contracting Hepatitis C, though about 10% of those infected do not have the typical risk factors.

Currently, use of an infected person’s nail clippers, toothbrush are considered a means of transmission though much less likely than septic medical practices (improperly disinfected equipment, reuse of septic infected catheters, needles) and the sharing of needles for drug use, tattooing, acupuncture.  Sexual contact is also a means of transmission.  The chief means of transmission currently is the sharing of IV needles though there are sporadic outbreaks from medical settings.

The fact that most infections are asymptomatic means that the disease continues to spread from those who do not know they are infected.

Signs and Symptoms

Hepatitis C can be a silent killer, possibly manifesting no symptoms for years until liver damage has advanced significantly.  These symptoms are: dark colored urine, light colored stools, nausea, fatigue, stomach pain, vomiting, and loss of appetite, diarrhea, abdominal pain, headache and jaundice (def).  A small minority of patients will have these symptoms in an acute infection which then becomes a chronic infection.

Those that are chronically infected (def) can have Glomerulonephritis (def), joint pain, Keratoconjuncitivits sicca (def), lichen planus, lymphoma cryoglobulinemia (def) which are extrahepatic manifestations of the disease.  Contracting another type of infection such has Hepatitis B or HIV/AIDS, not an unlikely scenario with high risk groups such as IV drug users, increases the death rate.

The major concern for HCV is that it causes cirrhosis (def) and is the primary cause of liver cancer in the U.S.  When the disease reaches those advanced stages the only recourse is liver transplant along with immunosuppression drugs which can allow the HCV to again overwhelm the host’s immune system, killing the patient.  It is difficult to get a liver transplant in the U.S. with the shortage of available donated organs and so those that are gravely ill, and to that extent less likely to survive a transplant, are those given priority.  Even under the best of circumstances, there are a number of risks associated with liver transplant.  It is for this reason that HCV is considered a major public health issue, because of the associated human and health care costs associated with this difficult illness.

Prevention and Treatment

There is no vaccine available for Hepatitis C as there is for Hepatitis A and Hepatitis B.  Avoidance of: shared needles, unprotected sex (def), especially with multiple partners, and ensuring aseptic medical practices are the best way to prevent the disease.  Pregnant women or those who expect to get pregnant, especially those with risk factors or who have had sexual partners with risk factors,  may want to get screened. 

The fact that Hepatitis C infection rates have remained steady through the 2000’s, with an expected upsurge in cirrhosis and hepatic Cellular Carcinoma for patients who have been infected 10-30 years, has made it clear that better educating health care professionals about the need for assessing of risk factors and screening will be an important part of preventing the worst outcomes of HCV as is public education and informing  those infected.

Diagnosis: 

Diagnosis is done by measuring for antibodies to HCV using a serologic assay and measuring for HCV’s nucleic acids using a molecular assay.  Management of HCV requires a sensitive quantitative assay of HCV RNA.  False positives occur rarely but if they do they are in populations with low incidence of HCV.  False negatives can occur in high risk populations such as those on hemodialysis, and those with HIV or who otherwise have suppressed immune systems.

Noteworthy is that HCV RNA tests are positive by 2 weeks after exposure while the antibody tests are not positive for 2-3 months due to the time necessary for adaptive immunity responses.  A genotype assay is necessary with a positive result to guide management of the disease.

Treatment:

Treatment responses and regimens are affected by a matrix of factors.  First, it is important to determine genotype of the HCV.  Genotypes 1a and 1b do not respond as well to current treatments as do Genotypes 2 and 3 and also have different early markers during treatment to predict positive

outcomes.  Genotype 1 can also have significant fibrosis (def) in as much as a quarter of the patients with normal amino transferase results.  Bridging fibrosis (def) indicates treatment is necessary because
it is a reliable predictor of later development of cirrhosis. The treatment regimen entails ill effects and
has variable results so it is also necessary to determine the extent of liver damage before committing to taking the treatment drugs.

The combination of Peg interferon Alfa and Ribavirin is the best way to control and prevent relapse of HCV, though responses can vary.  Peg interferon Alfa is a cytokine produced by recombinant DNA technology.  Ribavirin is an antiviral which inhibits DNA synthesis by being structurally similar to viral DNA but not allowing bonding of phosphate groups to nucleotides. 

There are 2 Peg interferon Alfas: Peg interferonAlfa 2a dosed at 180 μg/week by injection used to treat Genotypes 1, 2, and 3; and Peg interferon Alfa 2b dosed at 1.5μg/kg of bodyweight per week used to treat Genotype 4.  (The other Genotypes 5 and 6 are far less common internationally and have not been studied as much.)  Either is administered with Ribavirin.  Genotypes 2 and 3 can receive what is considered a low dose of Ribavirin, 800mg, along with the Peg interferon Alfa 2a, dosed as previously described.  Genotype 1 needs dosing based on weight:   for those under 75kg: 1000mg daily and for those at or over 75kg 1200mg/daily.  Genotype 1 needs a 48 week treatment regimen of above described doses and Genotype 2 and 3 need only a 24 week regimen.

Ultimately one is trying to attain a Sustained Viral Response (SVR) as defined by a measure, using a sensitive PCR assay at 24 weeks after end of full therapy, of HCV RNA in serum.  An early predictor of success in achieving SVR is both a Rapid Virological Response (RVR) (test with lower limit of 50 IU/mL findings of no detectable RNA of HCV at 4rth week of treatment) and Early Virological Response (EVR) (def): both reduction/or absence of HCV RNA in serum and equal or greater than 2 log reduction at 12th week of therapy).   While there is still a possibility of some developing cancer of the liver for patients who already have cirrhosis, the best outcome is a Sustained Viral Response  SVR (def).

Tools for Monitoring prior to and after anti viral treatment:

Chronic liver disease requires ongoing monitoring by non-invasive manners such as measurement of:
Platelet count (def)
Prothrombin time (def)
Liver Chemistry Panels
Quantitative liver function tests
X-rays
Serum markers for fibrosis
Serum markers for inflammation
Ultrasound can be used detect fibrosis (def) in some cases and inflammation in others but is not fully reliable to detect all cases of fibrosis.  The above non-invasive measures can place a patient in the earliest stages or the final cirrhosis stage, but the intermediate stages can only at this time be definitively tracked with a liver biopsy.   

Histological stages have 4 different measures:  the IASL, the Batts-Ludwig and the Metavir, with 4 stages each for the first three and the Ishak with 6.  The biopsy can help identify whether there is bridging fibrosis: fibrosis going central to portal or portal to portal, an indicator for necessity of treatment. 

The presence of Type I and Type II mixed cryoglobulinemia (def), an extrahepatic disease associated with HCV, requires treatment no matter what liver stage the HCV patient fall under.

HCV is a long-term illness so there is still much research to be done on ways to get the best treatment outcomes in the long-term, over decades.  Making sure that serum ALT levels are normal, having a lack of HCV RNA in serum as measured by a sensitive PCR-based assay and a low necroinflammatory score and stable fibrosis score are the desired outcomes.

BIBLIOGRAPHY

CDC Division of Viral Hepatitis, Statistics and Surveillance. “Disease Burden from Viral Hepatitis A, B, and C in the United States” Retrieved March 26, 2010 from:
http://www.cdc.gov/hepatitis/PDFs/disease_burden.pdf

CDC. “Hepatitis ABC Fact Sheet” Retrieved March 29, 2010 from:
http://www.cdc.gov/hepatitis/Resources/Professionals/PDFs/ABCTable_BW.pdf

CDC. “Surveillance for Acute Viral Hepatitis-United States 2007 MMWR Weekly. May 22, 2009; 58(SS-3) from
www.cdc.gov/mmwr

CDC. Table 1: Reported cases of acute viral hepatitis, by type and year,
United States, 1966-2003
http://www.cdc.gov/hepatitis/PDFs/US-surv_table.pdf

Ghany, Marc G., et al.  “AASLD* Practice Guidelines: Diagnosis, Management and Treatment of Hepatitis C: An Update.”  Hepatology, April 2009.  Retrieved March 24, 2010 from:
http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Diagnosis_of_HEP_C_Update.Aug%20_09pdf.pdf

ICTVdB Management (2006).00.026.0.03.001.  Hepatitits C virus.  In: ICTVdB-The Universal Virus Database, version 4.  Büchen-Osmond, C. (Ed), Columbia University, New York, USA
Retrieved on March 26, 2010 from:
www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB

Institute of Medicine of the National Academies. “Hepatitis and Liver Cancer: A National Strategy for the Prevention of Hepatitis B and Hepatitis C: Report Brief January 11, 2010.  Retrieved March 26, 2010 from:
http://www.iom.edu/~/media/Files/Report%20Files/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C/Hepatitis%20and%20Liver%20Cancer%202010%20%20Report%20Brief.ashx

Kaiser, Gary. Biology 230 Microbiology Lecture E. Text
Retrieved March 27, 2010 from:
http://student.ccbcmd.edu/courses/bio141/lecguide/index.html

NIH. Management of Hepatitis C: 2002, U.S.Department of Health & Human Services, National Institutes of Health, Consensus Conference Statement June 10-12, 2002.  Retrieved March 27, 2010 from:  http://consensus.nih.gov/2002/2002Hepatitisc2002116html.htm

NIH.  National Institute of Digestive, Diabetes and Kidney (NIDDK) Viral Hepatitis: A through E and Beyond.
http://digestive.niddk/nih/gov/ddiseases/pubs/viralhepatitis/index.htm

NIH. Hepatitis: What you need to know, U.S.Department of Health & Human Services, National Institutes of Health, National Institute of Digestive, Diabetes and Kidney
http://digestive.niddk/nih/gov/ddiseases/hepatitis_