eMedicine Specialties > Gastroenterology > Liver

Hepatitis C

Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Coauthor(s): Vinod K Dhawan, MD, FACP, FRCP(C), Professor, Department of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Professor of Medicine, Charles Drew University of Medicine and Science; Chief, Division of Infectious Diseases, MLK-Harbor Hospital
Contributor Information and Disclosures

Updated: Jun 18, 2009

Introduction

Background

The World Health Organization (WHO) estimates 170 million individuals worldwide are infected with hepatitis C virus (HCV). However, the prevalence of HCV infection varies throughout the world. For example, in 2000, Frank et al reported that Egypt has the highest number of reported infections, largely attributed to the use of contaminated parenteral antischistosomal therapy.1 This has led to a mean prevalence of HCV antibodies in persons in Egypt of 22%. According to the US Centers for Disease Control and Prevention, an estimated 1.8% of the US population is positive for HCV antibodies. Because 3 of 4 seropositive persons are also viremic, this corresponds to an estimated 2.7 million people with active HCV infection nationwide. Infection due to HCV accounts for 20% of all cases of acute hepatitis, an estimated 30,000 new acute infections, and 8000-10,000 deaths each year in the United States.

Medical care costs associated with the treatment of HCV infection in the United States are estimated to be more than $600 million a year. Most patients infected with HCV have chronic liver disease, which can progress to cirrhosis and hepatocellular carcinoma (HCC). Chronic infection with HCV is one of the most important causes of chronic liver disease (see Media file 1) and, according to a report by Davis et al from 2003, the most common indication for orthotopic liver transplantation (LT) in the United States.2

HCV is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family and Flavivirus genus. In 2001, Lauer and Walker reported that HCV is closely related to hepatitis G, dengue, and yellow fever viruses. HCV can produce at least 10 trillion new viral particles each day. RNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies. These represent minor molecular variations with only 1-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development.

The HCV genome consists of a single, open reading frame and 2 untranslated, highly conserved regions, 5'-UTR and 3'-UTR, at both ends of the genome. The genome has approximately 9500 base pairs and encodes a single polyprotein of 3011 amino acids that are processed into 10 structural and regulatory proteins (see Media file 2).

Structural components include the core and 2 envelope proteins, E1 and E2. Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, thought to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV.

The nonstructural components include NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7, whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. One region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity-determining region. These enzymes are critical in viral replication and are attractive targets for future antiviral therapy.

Six major HCV genotypes and numerous subtypes have been identified. Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40-80% of all isolates. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. Genotypes 2 and 3 are also found globally and account for a significant minority of infections. HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC.

The other genotypes have a more specific geographical distribution. Genotype 3 is found in Australia, the Indian subcontinent, and Thailand. Genotype 4 is the most prevalent genotype in Egypt and the Middle East. Genotype 5 is found in South Africa, and genotype 6 is more common in Southeast Asia, particularly in Hong Kong, Macao, and Vietnam. Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among Scottish persons who abuse intravenous drugs.

Currently, HCV is predominantly transmitted by means of percutaneous exposure to infected blood. In developed countries, most new HCV infections are related to intravenous drug abuse. The screening of blood donors for HCV antibody since 1990 has decreased the risk of transfusion-associated HCV infection to less than 1 case in 103,000 transfused units. With the use of more sensitive assays, such as polymerase chain reaction (PCR), Stramer et al reported in 2004 that the risk of acquiring HCV from blood transfusions is estimated to be 1 in 230,000 donations.3 The newer assays have decreased the window after infection to 1-2 weeks.

HCV may also be transmitted by means of acupuncture, tattooing, and sharing razors. Needlestick injuries in the health care setting result in a 3% risk of HCV transmission, but, according to Rischitelli et al in 2001, HCV prevalence among health care workers is similar to that of the general population.4 Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope, via dialysis, or during surgery, including organ transplantation before 1992. Yeung et al reported in 2001 that uncommon routes of transmission of HCV, which affect less than 5% of the individuals at risk, include high-risk sexual activity and maternal-fetal transmission.5 Co-infection with HIV type 1 appears to increase the risk of both sexual and maternal-fetal transmission of HCV. Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10% of cases.

Pathophysiology

The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells. In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from studies suggest at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C.

Frequency

United States

HCV infections account for approximately 30,000 new infections and 8000-10,000 deaths each year in the United States, as reported by Alter et al in 1999.6 Of new infections, 60% occur in persons who use intravenous drugs; less than 20% are acquired through sexual exposure; and 10% are due to other causes, including occupational or perinatal exposure and hemodialysis. The overall prevalence of anti-HCV antibodies in the United States is 1.8% of the population. Approximately 74% of individuals are positive for HCV RNA; this rate indicates that an estimated 4 million persons are infected with HCV and 2.7 million persons in the United States have chronic infection. Three fourths of these individuals are infected with HCV genotype 1.

International

More than 170 million individuals throughout the world are infected with HCV. The prevalence rates in healthy blood donors are 0.01-0.02% in the United Kingdom and northern Europe, 1-1.5% in southern Europe, and 6.5% in parts of equatorial Africa. Prevalence rates as high as 22% are reported in Egypt and are attributed to the use of parenteral antischistosomal therapy.

Mortality/Morbidity

Hepatitis C is the major cause of chronic hepatitis in the United States. HCV infections account for 20% of all cases of acute hepatitis. HCV accounts for more than 40% of all referrals to active liver clinics.

  • Niederau et al reported in 1998 that severe progression of hepatitis C to cirrhosis occurs in approximately 20% of patients who have chronic infection.7 Bellentani et al and Hourigan et al, both in 1999, reported that the rate and chance of progression is influenced by alcohol use, immunosuppression, sex, iron status, concomitant hepatitis, and age of acquisition (see Media file 3).8
  • HCC develops in 1-4% of patients with cirrhosis each year. El-Serag et al reported in 2003 that HCV is largely responsible for the increase in the incidence of HCC in the United States.9
  • In the United States, the number of deaths due to HCV-related complications has increased from fewer than 10,000 in 1992 to just fewer than 15,000 in 1999. According to Kim, as reported in 2002, this number is expected to increase in the future because of the current large pool of patients with chronic infections.10

Race

In the United States, HCV infection is more common among minority populations, such as African Americans and Hispanic persons, than other populations. Furthermore, in the United States, genotype 1 is more prevalent in African Americans than in other racial groups.

Sex

Females infected with HCV have somewhat better outcomes than their male counterparts.

Age

In the United States, 65% of persons with HCV infection are aged 30-49 years. Those who acquire the infection at a younger age have a somewhat better prognosis than those who are infected later in life.

Clinical

History

Most patients with chronic hepatitis C are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis from HCV infection frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus.

Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distension (ascites), and hematemesis or melena (variceal bleeding).

Physical

Most patients do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis.

  • Palmar erythema
    • Spider nevi
    • Dupuytren contracture
    • Asterixis
    • Leuconychia
    • Clubbing
  • Icteric sclera
    • Temporal muscle wasting
    • Fetor hepaticus
    • Enlarged parotid
    • Cyanosis
  • Gynecomastia
  • Paraumbilical hernia
    • Ascites
    • Caput medusae
    • Hepatosplenomegaly
    • Abdominal bruit
    • Small testes
  • Ankle edema
  • Scant body hair
  • Other clues - Excoriations, petechia, and tattoos

Causes

Hepatitis C is caused by a spherical, enveloped, single-stranded RNA virus belonging to the family Flaviviridae, genus Flavivirus.

More on Hepatitis C

Overview: Hepatitis C
Differential Diagnoses & Workup: Hepatitis C
Treatment & Medication: Hepatitis C
Follow-up: Hepatitis C
Multimedia: Hepatitis C
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

hepatitis C virus, HCV, HCV infection, non-A non-B hepatitis, NANB hepatitis, acute hepatitis, hepatitis, virus infection, viral infection, virus, chronic liver disease, hepatocellular carcinoma, hepatoma, HCC, cirrhosis, orthotopic liver transplantation, OLT, quasispecies, interferon, IFN, sustained virologic response, sustained virological response, SVR, HIV-HCV coinfection, HIV-HCV co-infection, IFN therapy, interferon therapy, pegylated interferon therapy, PEG-IFN, pegylated interferon, hepatitis C viremia, hepatitis viremia

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Contributor Information and Disclosures

Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Coauthor(s)

Vinod K Dhawan, MD, FACP, FRCP(C), Professor, Department of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Professor of Medicine, Charles Drew University of Medicine and Science; Chief, Division of Infectious Diseases, MLK-Harbor Hospital
Vinod K Dhawan, MD, FACP, FRCP(C) is a member of the following medical societies: American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Royal College of Physicians and Surgeons of Canada
Disclosure: Pfizer Inc None None

Medical Editor

George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine
George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians
Disclosure: Humana Press Consulting fee Consulting; Novartis Consulting fee Review panel membership

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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