Viral Hepatitis C: Introduction

Introduction

Figure 1. Location of liver in body

“Viral hepatitis," refers to infections that affect the liver and are caused by viruses. It is a major public health issue in the United States and worldwide. Not only does viral hepatitis carry a high morbidity, but it also stresses medical resources and can have severe economic consequences. The majority of all viral hepatitis cases are preventable.

Viral hepatitis includes five distinct disease entities, which are caused by at least five different viruses. Hepatitis A and hepatitis B (infectious and serum hepatitis, respectively) are considered separate diseases and both can be diagnosed by a specific serological test. Hepatitis C and E comprise a third category, each a distinct type, with Hepatitis C parenterally transmitted, and hepatitis E enterically transmitted. Hepatitis D, or delta hepatitis, is another distinct virus that is dependent upon hepatitis B infection. This form of hepatitis may occur as a super-infection in a hepatitis B carrier or as a co-infection in an individual with acute hepatitis B. Hepatitis viruses most often found in the United States include A, B, C, and D.

Because fatality from hepatitis is relatively low, mortality figures are a poor indicator of the actual incidence of these diseases. The Centers for Disease Control and Prevention estimated that approximately 400,000–600,000 people were infected with viral hepatitis during the decade of the 1990s.

Hepatitis plagued mankind as early as the fifth century BC. It was referenced in early biblical literature and described as occurring in outbreaks, especially during times of war. Toward the end of the nineteenth century, hepatitis was thought to occur as a result of infection of the hepatic parenchyma. The infectious nature of hepatitis was established after World War II. In the mid-1960s, Blumberg and colleagues discovered the surface antigen and antibody of hepatitis B. This Nobel Prize-winning research opened the door to our appreciation of the morphological and immunochemical features of other forms of viral hepatitis.

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General Info

What is Hepatitis C?
The hepatitis C virus (HCV) is a major cause of hepatitis (acute and chronic) and cirrhosis the world over. According to the Centers for Disease Control and Prevention, 21% of all acute viral hepatitis in the United States may be attributed to hepatitis C viral infection. Infection with hepatitis C almost always results in chronic infection. Sixty-seven percent of all cases develop chronic liver disease with accompanying elevation of liver enzymes. Hepatitis C viral infection is also thought to be a major contributing factor to hepatocellular carcinoma.

Discovered in 1990 as a causative agent for post-transfusion non-A, non-B hepatitis, ~3% of the U.S. population is now infected with hepatitis C (between 4–5 million seropositive individuals). There are approximately 30,000 new cases of acute hepatitis C diagnosed each year in the United States.

The hepatitis C virus (HCV) is a single-stranded RNA virus of the Hepacivirus genus in the Flaviviridae family (Figure 2).

Figure 2. Morphology of hepatitis C virus. E1, E2, envelope glycoproteins.

The genomic organization of the hepatitis C virus shows highly conserved 5’ and 3’ nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (Figure 3).

Figure 3. Genomic organization of hepatitis C virus.

Hepatitis C virus protease, helicase, and polymerase activities are also encoded in this region and are currently the focus of intense research to develop specific hepatitis C viral inhibitors. The half-life of HCV RNA is approximately 2 ½ hours with 1012 virions produced per day (Figure 4).

Figure 4. Hepatitis C life cycle animation. Click to start animation.

The viral replication of hepatitis C is error prone, which enables the production of genotypes (60–70% homology), quasi species (97–98% homology), and individual clonotypes (Figure 5). The genetic diversity increases over time and may ultimately lead to the emergence of more virulent or treatment-resistant strains of the virus.

Figure 5. Geographic distribution of Hepatitis C viral species.

The predominant mode of transmission for hepatitis C has shifted from post-transfusion infection to injection drug use. Other modes of transmission include nosocomial (e.g., in hemodialysis units), intranasal cocaine use, tattoos, body piercing, sexual transmission, and perinatal exposure (Figure 6).

Figure 6. Risk factors for acute infection with hepatitis C virus.

Symptoms
Viral hepatitis may develop without clinical signs or symptoms, or nonspecific symptoms may appear for a short time with or without jaundice. These symptoms may vary from nonspecific flu-like symptoms to fatal liver failure. Diagnosis of viral hepatitis often depends on an accumulation of findings considered together.

Early in the disease process, generally called the prodromal phase, some patients experience a serum-type sickness that may include fever, arthralgia, arthritis, rash, and angioneurotic edema. These symptoms usually occur 2–3 weeks before jaundice and generally subside before jaundice develops, although in some cases they may be concomitant with its appearance.

In the pre-icteric phase of viral hepatitis, patients may experience respiratory and gastrointestinal tract symptoms, which may include malaise, fatigue, myalgia, anterior, nausea, and/or vomiting. They may also experience moderate weight loss, headache, coryza, fever, or pharyngitis and cough. Many patients complain of midepigastric pain, right upper quadrant discomfort, or diarrhea. Also characteristic of this phase is the development of dark urine and the lightening of stool color. The preicteric phase may range from 2–3 days to 2–3 weeks.

The icteric phase is signaled by the development of jaundice. General constitutional symptoms may subside, however, there may be worsening of anorexia, nausea, and vomiting, along with scratching and irritated skin lesions related to pruritis.

Pathogenesis
The natural history of hepatitis C remains incompletely defined. Approximately 85% of acute hepatitis C viral infections become persistent (Figure 7).

Figure 7. Typical course of hepatitis C infection; ALT=alanine aminotransferase; PRC=polymerase chain reaction; EIA=enzyme immunoassay.

In most of these individuals, there is biochemical and histological evidence of chronic hepatitis in addition to circulating HCV RNA. Fifteen percent of acutely infected patients who recover may retain the hepatitis C viral antibodies for several years, whereas others will have no serological markers of the infection on extended follow-up. In a smaller group (approximately 27%), viremia is persistent (or possibly intermittent), but serum alanine aminotransferase (ALT) levels are usually normal (Figure 8).

Figure 8. Patterns of infection. ALT=alanine aminotransferase.

In a recent study evaluating the fibrosis progression/year (= fibrosis stage/duration of infection), this group appeared to have a slower median rate of progression of fibrosis (0.05 vs. 0.13 units in patient with elevated ALT levels, P<0.001). However, three patients with persistently normal ALT levels had cirrhosis (all heavy drinkers). In the group with persistently or intermittently elevated ALT, the median duration for disease progression was 13.7 10.9 years for chronic hepatitis, 20.6 10.9 years for cirrhosis, and 28.3 11.5 years for hepatocellular carcinoma. In a cross-sectional study of 2,235 patients in France, investigators found an increased rate of fibrosis progression with the following risk factors: age at infection > 40 years, daily alcohol use > 50 gm, and male gender. It was noted that the rate of fibrosis progression was not normally distributed, with 33% progressing to cirrhosis in less than 20 years, whereas 31% did not progress to cirrhosis for at least 50 years. No association was found between the progression of fibrosis and HCV genotype. Once patients develop cirrhosis, the rate of decompensation is 3.9% annually, the development of hepatocellular carcinoma occurs at an annual incidence of 1.4%, and mortality occurs at 1.9% per year (Figure 9).

Figure 9. Progression of hepatitis C infection.

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