Hepatitis C

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Hepatitis C
ICD-10	B17.1, B18.2
ICD-9	070.4, 070.5
OMIM	609532
DiseasesDB	5783
MedlinePlus	000284
MeSH	D006526

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Varun Kumar, M.B.B.S. [2]; Assistant Editor-In-Chief: Nina Axiotakis [3]{{#meta: itemprop="medicalWebPageAudiences" content="patient"}}{{#meta: itemprop="medicalWebPageSpecialities" content="cardiology"}}{{#meta: itemprop="medicalWebPageInfoTypes" content="symptoms,diagnosis,treatment,causes,prognosis,complications"}} Classification Classic::Classification Atypical::

Overview

Hepatitis Main Page
Hepatitis C
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Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
Risk Factors
Screening
Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian

Overview

Hepatitis C virus (HCV) is a single-stranded RNA virus that causes liver damage. Initially discovered in 1989, HCV was found to be a bloodborne infection that develops into a chronic state in most cases. Although the exact pathogenesis and life cycle of HCV are not well understood, it has been demonstrated that impaired innate and adaptive immunity to acute HCV may contribute to the development of chronic infection. While the transfusion of blood and blood products along with injectable therapy were considered the most common risk factors for HCV in the past, the use of illegal intravenous drugs is currently the most important risk factor. In the absence of treatment, chronic HCV leads to liver cirrhosis several years after the initial infection, a course complicated by decompensated liver failure or hepatocellular carcinoma. Other extra-hepatic manifestations are also common. Specific patient populations should be screened for HCV first using HCV serological testing or, rarely, directly by measuring HCV RNA in patients who have had previous HCV exposure, treatment-induced clearance, or immunosuppression. The diagnosis is made when tests for anti-HCV and HCV RNA both return positive results. Measures to slow the progression of liver disease, such as vaccines against other diseases and increased awareness of the risks associated with the use of alcohol or drugs that injure the liver should be taken following diagnosis. Classically, interferon (IFN) therapy was used to treat HCV, followed by the use of ribavirin. More recently, protease inhibitors emerged as effective drugs of choice for HCV infection.

Historical Perspective

The discovery of the hepatitis C virus was made based on early findings of patients with signs and symptoms of viral hepatitis lacking positive serologies for hepatitis A or B. These patients were originally described in 1974-5 as having "non-A, non-B viral hepatitis" (NANBH). It was not until 1989 that hepatitis C virus (HCV) was truly discovered when Qui-Lim Choo and colleagues successfully isolated the first cDNA clone 5-1-1 derived from the NANBH genome. The first interferon-alpha (INF-a) to treat HCV was developed in 1986 and approved in 1991. Approximately 10-15 years later, global efforts to reduce the burden of HCV were launched; worldwide campaigns were led by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC).

Pathophysiology

In cases of isolated acute HCV infection, the host immune system stimulates the secretion of interferon-alpha and the activation of natural killer cells, which is followed by the activation of the adaptive immune system. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis, which causes hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma has yet to be elucidated.

Causes

The hepatitis C virus (HCV) is the causative agent of hepatitis C. It is a member of the genus Hepacivirus that belongs to the Flaviviridae family. It is an enveloped, single-stranded RNA virus. The RNA genome acts as a template for viral replication and eventually, protein biosynthesis. Humans are considered the only natural hosts for HCV. The virus is primarily transmitted by exposure to contaminated blood.

Classification

HCV can be classified based on the isolated genotype and subtype. Six major genotypes have been identified. Several new genotypes and subtypes were recently discovered.

Epidemiology and Demographics

Hepatitis C is a major health problem that affects approximately 2 to 4 million people in the United States, 5 to 10 million people in Europe, and 12 million people in India. Approximately 150,000 new cases occur annually in the United States and in Western Europe, although incidence rates are difficult to estimate with accuracy given the asymptomatic nature of early stages of the disease. While the prevalence of the disease appears to be declining, hepatitis C is still highly prevalent in specific areas of the world. Egypt is the country with the highest prevalence of HCV, HCV-associated cirrhosis, and hepatocellular carcinoma, and the prevalence tends to increase with age, suggesting ongoing new cases of HCV. Approximately one-fourth of all cases of cirrhosis and hepatocellular carcinoma are attributed to HCV worldwide. Hepatitis C affects males and females equally.

Risk Factors

Risk factors for hepatitis C include intravenous drug use (most important), multiple blood transfusions prior to 1992, therapeutic injections for hemophilia prior to 1987, and work in the healthcare field (given that exposure to contaminated blood products is the most important mode of transmission).

Other, less common risk factors include occupational exposure to blood, such as contaminated needle sticks, Hemodialysis, solid organ transplantation from infected donors, birth to infected mother (in cases of detectable maternal HCV PCR at delivery), sexual intercourse with an infected partner, sexual intercourse with multiple partners, HIV infection, and tattoos or piercings with infected needle sticks.

Screening

People living in regions highly prevalent with HCV and who have engaged in high-risk behaviors should be screened. Screening by serological testing, confirmed by nucleic acid amplification (NAT) for HCV RNA, is required. Additionally, screening for other bloodborne infections, such as HBV and HIV, is required once a diagnosis is made. The ideal frequency of testing in these patients is unclear and should be personalized according to the frequency of a patient's exposure to risk.

Differentiating Hepatitis C from other Diseases

Hepatitis C must be differentiated from other diseases that cause hepatic injury and abnormal liver function tests such as other viral hepatitides (Hepatitis A, Hepatitic B, and Hepatitis E), and non-viral etiologies (e.g., alcoholic liver disease, non-alcoholic steatohepatitis, drug-induced liver injury, autoimmune hepatitis, and hepatocellular carcinoma).

Natural History and Prognosis

The majority of individuals infected with HCV will become chronic carriers. The most common complications of HCV are hepatic, including liver cirrhosis years after the onset of infection and the consequent development of hepatocellular carcinoma. Other classical extrahepatic manifestations, such as cryoglobulinemia, lichen planus, membranoproliferative glomerulonephritis, and porphyria cutanea tarda are also complications of chronic HCV infection. Treatment is necessary for patients with chronic stable HCV infection; otherwise, prognosis is poor and progression of the disease may be fatal.

Treatment

The treatment of hepatitis C has changed dramatically over the past decade. Whereas relatively new protease inhibitors telaprevir and boceprevir were added to the regular regimen of IFN and ribavirin in 2011 to treat patients with genotype 1 HCV, newer oral agents sofosbuvir and simeprevir have demonstrated greater efficacy in viral clearance along with a better safety profile. New guidelines from the AASLD and the IDSA have endorsed the use of these oral agents (particularly sofosbuvir) as first-line agents in the treatment of chronic HCV in both relapsers and treatment-naive patients.

Historical Perspective

Hepatitis Main Page
Hepatitis C
Home
Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
Risk Factors
Screening
Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian

Overview

The discovery of the hepatitis C virus was made based on early findings of patients with signs and symptoms of viral hepatitis lacking positive serologies for hepatitis A or B. These patients were originally described in 1974-5 as having "non-A, non-B viral hepatitis" (NANBH). It was not until 1989 that hepatitis C virus (HCV) was truly discovered when Qui-Lim Choo and colleagues successfully isolated the first cDNA clone 5-1-1 derived from the NANBH genome. The first interferon-alpha (INF-a) to treat HCV was developed in 1986 and approved in 1991. Approximately 10-15 years later, global efforts to reduce the burden of HCV were launched; worldwide campaigns were led by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC).

Discovery of Non-A, Non-B Viral Hepatitis

In the early 1960s, scientists only differentiated between hepatitis A, an acute infection of short incubation period transmitted via the fecal-oral route, and hepatitis B, a potentially chronic infection of long incubation period transmitted via blood exposure. Consequently, the discovery of hepatitis C only occurred with the availability of diagnostic assays in the early 1970s. In 1974-5, the works of Alfred Prince, Stephen Feinstone, and Harvey Alter led to the new discovery that was termed "non-A, non-B viral hepatitis" (NANBH) when serological markers for hepatitis A and B were both absent in patients with signs and symptoms of viral hepatitis. Shortly after, studies scrutinizing the new discovery revealed that most patients with NANBH had been exposed to blood transfusions and hepatic cirrhosis ensued in as many as 20% of these patients.

With no techniques available with which to isolate the virus, the infective potential and mode of transmission of NANBH were later confirmed in 1978 when chimpanzees were infected with the virus following injection of human blood from patients confirmed to have the disease. Experiments using chimpanzee models contributed to the discovery of various NANBH variants and agents, and allowed scientists to study the pathological aspects of hepatic injury in these infections.

Discovery of Hepatitis C Virus

The attempt to discover the first NANBH antibodies persisted for several years. Although the virus was originally described in the early 1970s, the identification of NANBH-specific antibodies did not occur until 1985 by Yohko Shimizu and colleagues. In 1989, the full isolation of a cDNA clone 5-1-1 derived from NANBH genome was finally successful. Qui-Lim Choo and colleagues were able to construct a random-primed complementary DNA (cDNA) from plasma containing an NANBH agent, showing that the virus is a positive-stranded RNA molecule composed of of 10,000 nucleotides. With the isolation of the new agent, hepatitis C virus (HCV) was discovered and the term replaced NANBH for the first time in 1989. In the early 1990s, HCV was then classified into 6 major genotypes and several subtypes. Due to similarity with other RNA viruses, it was considered a type member of the genus Hepacivirus within the family Flavividae.

Sequelae Following HCV Discovery

Following its discovery, blood tests were available by 1990 to detect the presence of HCV in blood products, to determine chronicity, and to reveal its association with such cancers as hepatocellular carcinoma and non-Hodgkin's lymphoma. Worldwide efforts to prevent the transmission of HCV have been somewhat successful in reducing the global burden of HCV.

Global Awareness Campaigns

In 2007, the World Health Organization (WHO) declared July 28 "World Hepatitis Day" and the Centers for Disease Control and Prevention (CDC) launched its national "Know More Hepatitis" campaign on July 28, 2011 to educate individuals born between 1945-1965 about HCV and launched its "Hepatitis Testing Day" on May 19, 2012.

Use of First Antiviral Drug for HCV

Even before the identification of the virus in 1989, the first effort to develop interferon-alpha (IFN-a) treatment against HCV was initiated in 1986 by Jay Houston Hoofnagle and colleagues. The drug was finally approved by the Food and Drug Administration (FDA) for HCV treatment in 1991 at a dose of 3 million units subcutaneously three times weekly for 6 months. Ribavirin was first used to treat HCV in 1997; the drug demonstrated a decrease in aminotransferase levels and a good safety profile, despite its lack of antiviral activity as monotherapy. The FDA approved the use of combination therapy of interferon alpha and ribavirin in 1998. Finally, pegylated interferon, which has a higher concentration and longer half life than interferon, was approved for use in 2001. Newer HCV protease inhibitors, such as telepravir, were developed in 2007.

References

Pathophysiology

Hepatitis Main Page
Hepatitis C
Home
Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
Risk Factors
Screening
Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Seyedmahdi Pahlavani, M.D. [7], Javaria Anwer M.D.[8]

Overview

In isolated acute HCV infection, the host immune system stimulates the secretion of interferon alpha and the activation of natural killer cells, which is followed by the activation of the adaptive immune system. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis, which cause hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma has yet to be elucidated.

Transmission

The transmission of HCV can be defined as percutaneous, sexual, healthcare-associated, or maternal-infant in nature.

Percutaneous Transmission

• Blood and blood components transfusion
  • More than 90% of seronegative recipients who are transfused with blood from HCV-antibody positive donors will acquire infection.
• Contaminated shared needles among intravenous drug users
  • Before 1992, at least two-thirds of new HCV infections in the United States were associated with illicit drug use; the number has since decreased significantly.
• Chronic hemodialysis
  • The frequency of anti-HCV in patients on hemodialysis ranges from less than 10% in the United States to 55% to 85% in Jordan, Saudi Arabia, and Iran.

Sexual Transmission

• HCV RNA has been detected in semen and saliva. People with multiple sexual partners and commercial sex workers have a high HCV prevalence.

Health care Associated

• Nosocomial transmission has been observed under several different conditions (e.g. needle stick, organ transplant, during surgery); now, however, because of infection control protocols, nosocomial transmission of HCV is rare except in cases of breach of protocols.

Maternal Infant Transmission

• Perinatal transmission frequency ranges from 0% to 4% in larger studies.

HCV Clearance and Persistence

Acute viral infection and HCV replication triggers the activation of host immune responses, first by secretion of type I interferon alpha (IFN-alpha) and activation of natural killer (NK) cells. Nonetheless, secretion of endogenous IFN does not seem to effectively inhibit HCV replication.

HCV proteins play a crucial role in inhibiting IFN-alpha effectors, such as IFN regulatory factor-3 (IRF-3), double stranded RNA-dependent protein kinase (PKR), and the JAK-STAT signaling pathway. More importantly, chronic carriage of HCV is associated with impaired activation of NK cells despite IFN-alpha secretion. It is believed that the cross-linking of CD81 and the envelope protein E2 of the virus is a key mechanism by which NK cells are inactivated and INF-gamma is not produced by these cells.

The activation of IFN-gamma is a prerequisite for the appropriate clearance of HCV. When activation occurs normally, antibodies start to form 7-31 weeks later. While most epitopes for antibodies have not been discovered yet, hypervariable region 1 (HVR1) of the E2 envelope glycoprotein was found to be a target for anti-HVR1 antibodies. Antibodies play a role in clearing the virus from the host. It is currently unknown whether "escape" mechanisms are present in HCV that favor persistent HCV infection despite an adequate antibody response.

Similarly, the activation of the CD4+ and CD8+ T-cell response is required for viral clearance. This cellular response allows for the development of long-term immunity against HCV. Studies also proved that delayed or inadequate activation of T-cell response is associated with persistence of infection. It is not known why T-cell response may fail in response to acute infection, but it is hypothesized that persistence might be related to viral inhibition of T-cell maturation, defective dendritic cells, and/or failure of interleukin (IL) 12 activation.

Liver Injury and Cirrhosis, and Hepatocellular Carcinoma

HCV is directly associated with hepatic steatosis, which is fat accumulation in the liver. It seems that core proteins may play a role in regulating lipid accumulation in hepatocytes, contributing to steatosis. However, steatosis is not observed in all genotypes of HCV infection; it is classically described in genotype 3, which perhaps is the only genotype that has a direct role in the development of steatosis irrespective of alcohol consumption or metabolic elements. Apart from steatosis, HCV per se has not been shown to have damaging effects on hepatocytes. The viral burden also does not seem to be directly related to the extent of liver injury.

In chronic hepatitis C infections, the local immune response leads to portal lymphoid infiltration and chronic inflammation, which give way to bridging necrosis and degenerative lobular lesions. Hepatic injury is directly associated with the degree of Th1 cytokine expression. The adaptive immune system, namely the cytotoxic T-cell response, injures infected cells as well as bystander cells. Nonetheless, it has not been confirmed whether the number of cytotoxic T cells is associated with the extent of liver injury.

Chronic inflammation ultimately leads to fibrogenesis due to deposition extracellular matrix elements in hepatic parenchyma. It is unknown whether viral components are directly responsible in the particular mechanism of hepatic cirrhosis in chronic HCV infection; although cirrhosis is definitely worsened in HCV patients who are also exposed to other risk factors, such as alcohol, obesity, and HIV.

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) occurs following chronic HCV infection complicated by liver cirrhosis. The precise role of HCV components in the development of HCC is poorly understood. Pinpointing which viral protein is directly related to carcinogenesis has been difficult, but studies have shown that NS3, NS4B, and NS5A all have oncogenic properties.

Histology

Click on the arrow to view the pathologic findings in viral hepatitis: {{#ev:youtube|_hXvbpSxFZw}}

Mechanisms involved in extra-hepatic manifestations

• Cryoglobulinemic vasculitis: Chronic antigen stimulation reduces the threshold for activation and proliferation of B-lymphocyte and induces Bcl-2 activation and t(14;18) translocation. It results in decreased apoptosis. As a result, CD21−CD27+ cells produce antibodies against the Fc portion of IgG, forming immune complexes that precipitate in small blood vessels.
• B-cell lymphoma: A continuous HCV antigen stimulation and permanent genetic damage caused by viral proteins cause clonal proliferation of CD21−CD27+. It also down-regulates tumor-suppressive signals (such as, microRNA-26b). Oncogenic signals are further enhanced and additional tumor suppressor genes such as Bcl-6, p53, and β-catenin undergo mutation. Hence, the reduced levels of caspase 3, 7, and 9 reduce their sensitivity to Fas-induced apoptosis.
• Cardiovascular disease: Local vascular damage is caused by an increased expression of adhesion molecules on endothelial surface. Smooth cells in the media proliferate and apoptosis is inhibited, with local macrophages producing proinflammatory cytokines and free radicals. These processes result in accelerated atherosclerosis, procoagulant effects, and lead to major cardiovascular events.
• Chronic kidney disease: Direct HCV cytopathic effect, chronic inflammation from atherosclerosis and insulin resistance, endothelial and mesangial inflammation, and podocyte and tubular injury caise CKD. Cryoprecipitates deposit at glomeruli also manifested as type I membranoproliferative glomerulonephritis.
• Type 2 diabetes: Caused by both hepatic and peripheral insulin resistance. In the liver, HCV leads to PI3K-AKT insulin-signaling pathway reduction via insulin receptor substrate 1 inhibition and impaired Glut2–mediated hepatic glucose intake. In the extrahepatic tissue, insulin resistance is a consequence of soluble endocrine mediators released by hepatocytes. Up-regulation of TNF, G6P, and resistin, with an imbalance in the adipocytokine profile, increases gluconeogenesis in these sites.

References

Epidemiology and Demographics

Hepatitis Main Page
Hepatitis C
Home
Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
Risk Factors
Screening
Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Seyedmahdi Pahlavani, M.D. [10], Javaria Anwer M.D.[11]

Overview

Hepatitis C is a major health problem that affects approximately 2 to 4 million people in the United States, 5 to 10 million people in Europe, and 12 million people in India. Approximately 150,000 new cases occur annually in the United States and in Western Europe, although accurate incidence rates are difficult to estimate given the asymptomatic nature of the early stages of the disease. While the prevalence of the disease appears to be declining, hepatitis C is still highly prevalent in certain areas of the world. Egypt is the country with the highest prevalence of HCV, HCV-associated cirrhosis, and hepatocellular carcinoma, and the prevalence tends to increase with age, suggesting ongoing development of new cases of HCV. Approximately one-fourth of all cases of cirrhosis and hepatocellular carcinoma are attributed to HCV worldwide. Hepatitis C affects males and females equally.

Epidemiology and Demographics

Incidence and Prevalence

• According to the World Health Organization (WHO), approximately 3% of the global population are infected with chronic hepatitis C virus (HCV). More than 170 million people are infected chronically around the world. The prevalence of HCV varies among different nations; for example, 1.3% to 1.6% of the U.S. population are affected, while up to 30% of Egypt population are infected with hepatitis C virus.
• Figures in individual countries also vary greatly: Approximately 2-4 million persons are infected with chronic HCV in the United States, 5-10 million in Europe, and more than 10 million in India.

• Acute HCV infection follows an asymptomatic course, which makes the accurate determination of HCV incidence difficult. Additionally, many countries lack sufficient epidemiological data. Nonetheless, it is estimated that approximately 150,000 new cases are reported in the United States and Western Europe annually, whereas the incidence in Japan is as high as 350,000 new cases each year. More than 60-80% of patients with HCV infection become chronic carriers of the disease, with an overall number of chronic carriers reaching approximately 170 million patients. The trend today is marked by a progressive decrease in new HCV infections, characterized by a remarkable 80% decrease since the infection was first discovered in 1989-1990.
• In 2014, a total of 2,194 cases of acute hepatitis C were reported to the CDC from 40 states.
• The overall incidence rate for 2014 was 0.7 cases per 100,000 people, an increase from 2010–2012.

CDC - Incidence and Prevalence of HCV - Source: https://www.cdc.gov/

Prevalence of HCV rises significantly in specific populations:

• Intravenous drug users: > 70% (Accounts for most modern cases of HCV infection)
• Hemophilia patients: > 70%
• Hemodialysis: 20-30%

Of note, nosocomial sources of HCV infection, such as infected blood and surgical products, have been significantly reduced due to the increased testing of products prior to utilization.

CDC figures for sources of infection in the US - Source: https://www.cdc.gov/

• The morbidity associated wth chronic hepatitis C, mainly due to complications is estimated to be 350,000 liver-related deaths per year.

Age

• The age of infected patients varies across regions. In the United States, Australia, and Western Europe, more than 65% of HCV infections are observed in patients between 30-50 years. These numbers suggest that most cases of HCV in these regions occurred before 1990. On the other hand, there is an increase of HCV prevalence with age in countries such as Turkey, Spain, Italy, Japan, China, and Egypt. Most patients in these countries are older than 50 years of age.
• In 2014, among all age groups, people ages 20–29 years had the highest rate (2.20 cases per 100,000 people) and people aged 0–19 and ≥60 years had the lowest rate (0.12 cases per 100,000 people) of acute hepatitis C.

Gender

In 2014, rates of HCV among males and females in the United States were 0.8 and 0.7 cases per 100,000 people, respectively.

Morbidity and Mortality

Approximately 27% of cases of cirrhosis and 25% of hepatocellular carcinoma (HCC) are attributed to chronic HCV infection.

Geographic Distribution

HCV is a global disease. The most highly endemic region of HCV—especially genotype 4a—is Egypt, due to a history of non-hygenic medical and paramedical practices in the country. As many as 25% of Egyptian blood donors are chronic carriers of HCV infection. In contrast, the United Kingdom and Scandinavia have a low prevalence of HCV compared to other regions.

In some countries, HCV is prevalent in specific regions rather than the entire counrty. Such patterns are observed in Italy, China, and Japan.

References

Risk Factors

Hepatitis Main Page
Hepatitis C
Home
Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
Risk Factors
Screening
Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [12]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian;Javaria Anwer M.D.[13]

Overview

The most potent risk factor in the development of hepatitis C is intravenous drug use. Other risk factors include occupational exposure to blood, sexual intercourse with infected individuals, multiple bloods transfusions prior to 1992, and HIV infection.

Risk Factors

Percutaneous exposure to blood is the primary mode of HCV transmission. The following are the most important risk factors for HCV infection::

• Individuals are majorly infected via percutaneous exposure to infected blood. Most persons with HCV were infected.
• Injecting drug use is the most important risk factors nowadays
• Transfusion of blood and blood products, especially before 1992
• Unsafe therapeutic injections, especially in hemophilia patients prior to 1987

Other, less important risk factors include:

• Hemodialysis (Higher rates of infection are observed)
• Solid organ transplantation from infected donors
• Occupational exposure to blood, such as contaminated needle sticks
• Birth to infected mother in cases of detectable maternal HCV PCR at delivery (at the rate of 4%–5%). Breastfeeding is not associated with the transmission.
• Sexual intercourse with infected partner
• Sexual intercourse with multiple partners
• HIV infection
• Tattoo or piercing with infected needle sticks (low risk for transmission after strict infection control measures)

References

Screening

Hepatitis Main Page
Hepatitis C
Home
Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
Risk Factors
Screening
Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [14]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian

Overview

People living in regions with high HCV prevalence and who have engaged in high-risk activities should be screened. Screening by serological testing, confirmed by nucleic acid amplification (NAT) for HCV RNA, is required. Additionally, screening for other bloodborne infections, such as HBV and HIV, is required once the diagnosis is made. The ideal frequency of testing in these patients is unclear and should be individualized according to the frequency of exposure to risk.

Screening

Initial Testing

Screening for HCV is performed by HCV serological testing. In patients who test positive, a confirmation for chronic HCV status is required by nucleic acid amplification (NAT) or HCV RNA. HCV RNA may be directly tested in immunocompromised patients or patients who already had spontaneous or treatment-related clearance.

Screening for other infections, such as HBV and HIV, is also indicated when patients are identified as HCV-positive. In some endemic areas and high-risk populations, screening for tuberculosis (TB) is also warranted.

Interpretation of Screening Results

• If an anti-HCV test is negative and patients are suspected to have liver disease, a follow-up HCV antibody or HCV RNA test is recommended if HCV exposure occurs within 6 months.

• If an anti-HCV test is positive but HCV RNA is negative, patients have no evidence of active infection.

• If an anti-HCV test is positive and HCV RNA is positive, a diagnosis of HCV infection is made. Quantitative HCV RNA tests should be performed before initiation of antiviral therapy to document baseline levels of viremia. Additionally, HCV genotyping is recommended to guide therapy.

Frequency of Screening

The ideal frequency of testing in patients is unclear and should be individualized according to frequency of exposure to risk. In patients who use intravenous drugs or HIV-positive men who have unprotected sex with men, annual screening may be considered.

Summary of Screening Recommendations

American Association for the Study of Liver Disease (AASLD) - Infectious Diseases Society of America (IDSA) "Recommendations for Testing, Managing, and Treating Hepatitis C": 2014

According to the AASLD - IDSA recommendations in 2014, the following patients should be screened for HCV:

• People born between 1945 and 1965

Risk Behaviors

• Injection-drug use (current or ever, including those who injected once)
• Intranasal illicit drug use

Risk Exposures

• Long-term hemodialysis (ever)
• Getting a tattoo in an unregulated setting
• Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-infected blood
• Children born to HCV-infected women
• Prior recipients of transfusions or organ transplants, including persons who:
  • were notified that they received blood from a donor who later tested positive for HCV infection
• received a transfusion of blood or blood components or underwent an organ transplant before July 1992
• received clotting factor concentrates produced before 1987
• were ever incarcerated

Other Medical Conditions

• HIV infection
• Unexplained chronic liver disease and chronic hepatitis including elevated alanine aminotransferase levels

World Health Organization "Guidelines for the Screening, Care, and Treatment of Persons with HCV": 2014

Generally, the World Health Organization (WHO) Guidelines for the Screening, Care, and Treatment of Persons with Hepatitis C Infection published on April 2014 recommends HCV screening for all people living in regions of high HCV prevalence with positive history for risk exposure and behavior.

Screening includes:

• Persons who received medical or dental interventions in health-care settings where infection control practices are substandard
• Persons who received blood transfusions prior to the time when serological testing of blood donors for HCV was initiated
• Persons who received blood transfusions in countries where serological testing of blood donations for HCV is not routinely performed
• Persons who inject drugs (PWID)
• Persons who have had tattoos, body piercings, or scarification procedures are done where infection control practices are substandard
• Persons with HIV infection
• Persons who have used intranasal drugs
• Prisoners and previously incarcerated persons

References

Causes

Hepatitis Main Page
Hepatitis C
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History & Symptoms
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Ongoing Trials at Clinical Trials.gov
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Risk calculators and risk factors for Hepatitis C

This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Hepatitis C.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [15]

Overview

Hepatitis C infection is caused by the hepatitis C virus.

Hepatitis C Virus

Viral Characteristics

The hepatitis C virus (HCV) is a member of the genus Hepacivirus that belongs to the Flaviviridae family. It is an enveloped, single-stranded RNA virus that measures approximately 60 nm in diameter.

Mode of Transmission

HCV is primarily transmitted by blood. Exposure to blood is observed primarily in healthcare settings, such as in blood transfusions, surgical procedures, needle injuries, and hemodialysis. Also, the role of intravenous drug use has recently emerged as a great risk for viral transmission after the relatively successful control of nosocomial HCV transmission.

Life Cycle

Humans are considered the only natural hosts for HCV. The full life cycle of the virus is poorly understood due to difficulty to culture in vitro. The expression of E1-E2, two important envelope glycoprotein complexes, on the surface of HCV allows the virus to interact with host-cell molecules (glycosaminoglycans) by acting as ligands for cellular receptors, such as tetraspanin CD81, scavenger receptor class B type I (SR-BI), and mannose binding lectins DC-SIGN and L-SIGN. This interaction is believed to have a crucial role in cell recognition and cellular tropism. The exact mechanism by which viral genome enters the host cell is poorly understood, but it is believed to be via receptor-mediated endocytosis. Then envelope glycoproteins utilize pH-dependent mechanisms to mediate fusion of the viral envelope using endosomal membrane. As soon as it is released into the cytoplasm, the viral nucleocapsid uncoats by unknown mechanisms.

Template HCV RNA allows viral replication to take place and protein synthesis is thus facilitated. Cap-independent protein translation takes place when ribosomal 40S subunit binds to internal ribosome entry site (IRES). IRES is a stem-loop structure that is located at the 5' untranslated region (UTR) of the virus and the initial 30-40 nucleotides of the viral core-encoding region. Nonetheless, full polyprotein translation also requires the use of 80S ribosomes and the viral 3' UTR, both of which presumably play a role in regulation of the translational process.

Translation is accompanied by co-translational processes and followed by post-translational processes, all of which yield a total of 10 mature proteins.

The following proteins are produced:

Structural Proteins:

• Core (C) protein

• Envelope 1 (E1) glycoprotein

• Envelope 2 (E2) glycoprotein

C, E1, and E2 are separated from the remaining 7 non-structural proteins by the activity of p7, a small membrane polypeptide that belongs to viroporin family. The 3 proteins are released by the activity of signal peptidases mediated by the host cell.

Non-Structural (NS) Proteins:

• NS2: Zn-dependent proteinase

• NS3: Serine-dependent proteinase, helicase, and NTPase

• NS4A: Cofactor NS3 proteinase

• NS4B: Membrane anchor

• NS5A: Regulation of RNA polymerase activity and inhibition of antiviral activity of interferon

• NS5B: RNA-dependent RNA polymerase

• p7: Separation of structural from non-structural proteins and possible formation of ion channel

Non-structural proteins NS3 to NS5B play an important role in the formation of a replication complex that includes an intracellular "membranous web", at least partially derived from host endoplasmic reticulum. The replication complex is responsible for synthesis template negative-strand RNA and consequent synthesis of its positive-strand counterpart. These RNA molecules are then enclosed in new virions.

Formation of Nucleocapsid and Envelope

New HCV nucleocapsid is formed by the action of core protein C along with viral genomic positive-strand RNA. The envelope of the newly formed nucleocapsid is later formed by budding action into the lumen of the endoplasmic reticulum. Nonetheless, envelope glycoproteins do not yet mature early on at this stage. When new virions are exported outside the host cell, via cellular secretory mechanisms, glycoproteins of the envelope finally mature.

References

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [16]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian

Overview

Hepatitis C must be differentiated from other diseases that cause hepatic injury and abnormal liver function tests such as other viral hepatitides (Hepatitis A, Hepatitis B, and Hepatitis E) and non-viral etiologies such as alcoholic liver disease, non-alcoholic steatohepatitis, drug-induced liver injury, autoimmune hepatitis, hepatocellular carcinoma, liver abscess, pancreatitis, and bowel obstruction.

Differential Diagnosis

The differential diagnosis of hepatitis C includes other etiologies of viral hepatitis and non-viral etiologies:

Viral Hepatitis Differential Diagnosis

• Viral Hepatitis A
• Viral Hepatitis B
• Viral Hepatitis D
• Viral Hepatitis E

Non-Viral Hepatitis Differential Diagnosis

• Autoimmune hepatitis
• Alcoholic liver disease
• Non-alcoholic steatohepatitis (NASH)
• Drug-induced liver injury (DILI)
• Liver abscess
• Hepatocellular carcinoma
• Cholelithiasis
• Cholecystitis
• Cholangitis
• Chronic biliary disease
• Trauma
• Abdominal aneurysm
• Gastritis
• Gastroenteritis
• Peptic ulcer disease
• Bowel obstruction
• Pancreatitis
• Pancreatic cancer
• Malignant lymphoma
• Hereditary metabolic disorders (Wilson disease, alpha-1 antitrypsin deficiency)

Differential diagnosis of jaundice as one pf symptoms of hepatitic C are:

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALK BLR Indirect BLR Direct Viral serology Jaundice Hepatocellular Jaundice Liver infiltration: Hemochromatosis, amyloidosis + - -/+ - ↑ ↑ ↑/N ↑/N N - Ferritin ↑ in hemochromatosis Liver biopsy Wilson's disease + - -/+ - ↑ ↑ N ↑/N N - Serum cerulloplasmin ↑ Liver biopsy Viral hepatitis - -/+ - - ↑ ↑ N ↑/N N + Specific viral antibody for each type - Alcoholic hepatitis - -/+ -/+ - ↑↑ ↑ N ↑/N N - - - Drug induced hepatitis - -/+ - - ↑ ↑ N ↑/N N - - - Autoimmune hepatitis -/+ - - -/+ ↑ ↑ N ↑/N N - Anti-LKM antibody Liver biopsy Cirrhosis -/+ -/+ -/+ - ↑ ↑ ↑/N ↑/N ↑/N -/+ Low platate Small liver on ultrasond Nonalcoholic steatohepatitis -/+ - - - ↑ ↑ N ↑/N N - High lipids liver biopsy Ischemic hepatopathy -/+ - -/+ - ↑ ↑ N ↑/N N - Cardiovascular risk factors Clinical setting Cholestatic Jaundice Common bile duct stone -/+ - + + N N ↑ N ↑ - Dilated ducts on sono CT/ERCP Hepatitis A cholestatic type - -/+ + + N N ↑ N ↑ + HAV- AB Abdominal ultrasound EBV / CMV hepatitis - -/+ + + N N ↑ N ↑ + Positive serology - Primary biliary cirrhosis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - AMA positive Liver biopsy Primary sclerosing cholangitis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - Pos. autoantibodies Beading on MRCP, Liver biopsy Sickle cell disease + - - +/- N/↑ N/↑ ↑ N ↑ - Genetic testing Pancreatic carcinoma + - -/+ -/+ N/↑ N/↑ ↑ N ↑ - - CT scan for diagnosis AIDS cholangiopathy - - -/+ -/+ N/↑ N/↑ ↑ N ↑ - Pos. HIV Sono or ERCP for diagnosis Parasites induces cholestasis - - -/+ -/+ N/↑ N/↑ ↑ N ↑ - Ab or parasite serology Sono or ERCP for diagnosis Intrahepatic cholestasis of pregnancy -/+ - -/+ + ↑ ↑ ↑ N ↑ - Low PLT, Neg viral serology Diagnosed clinically Isolated Jaundice Crigler-Najjar type 2 + - - - N N N ↑ ↑ - Genetic testing Gilbert + - - - N N N ↑ ↑ - Genetic testing Rotor syndrome + - - - N N N N ↑ - Genetic testing Liver biopsy Dubin-Johnson syndrome + - - - N N N N ↑ - Genetic testing Liver biopsy Hereditory spherocytosis + - -/+ - N N N ↑ N - Genetic testing Osmotic fragility G6PD deficiency + - - - N N N ↑ N - Genetic testing Thalassemia + - - - N N N ↑ N - Genetic testing Paroxismal nocturnal hemoglobinoria - - - - N N N ↑ N - Flocytometery Immune hemolysis - -/+ - - N N N ↑ N - Autoantibodies Hematoma - -/+ - - N N N ↑ N - Anemia Truma or surgery in history

Differential diagnosis of cirrhosis if happened in hepatitis C based on altered hepatic function are:

Condition	Differentiating signs and symptoms	Differentiating Tests
Cirrhosis	Abdominal pain and bloating Menstrual irregularities Symptoms of hypogonadism: Impotence Infertility Testicular atrophy Loss of libido Easy bruisability Decompensated cirrhosis may present with Jaundice Increase in abdominal girth due to ascites Pruritus Signs of upper gastrointestinal bleeding: Hematemesis Hematochezia Melena Symptoms due to hepatic encephalopathy: Altered mental status Confusion Sleep disturbances	Ultrasound findings in cirrhosis are as follows: Changes in liver contour: shrunken, irregular appearance Non homogeneous appearance of the hepatic tissue Increased surface nodularity Increase in echogenecity from focal fatty infiltration Atrophy of the right lobe and hypertrophy of the caudate or left lobe Splenomegaly Ascites Varices Hepatic or portal vein thrombosis Abdominal MRI may also be helpful in the diagnosis of portal hypertension. Findings on MRI suggestive of cirrhosis with portal hypertension include: Cirrhotic liver, as shrinkage and atrophy in liver Re-canalized umbilical vein--pathognomonic Dilated portal vein and/or splanchnic veins Esophageal varices Collaterals in any abdominal organ Splenomegaly Ascites Transient elastography and the Acoustic Radiation Force Impulse (ARFI) technique are well-established methods for the staging of fibrosis in various liver diseases:   The FibroScan (transient elastography) uses elastic waves to determine liver stiffness which theoretically may be converted into a liver score. The FibroScan produces an ultrasound image of the liver (from 20-80mm) along with a pressure reading (in kPa). Transient elastography is much faster than a biopsy (usually lasts 2.5-5 minutes) and is completely painless. Findings on transient elastography may show reasonable correlation with the severity of cirrhosis: Increasing scarring of the liver is associated with increasing "stiffness" of the tissue.
Constrictive pericarditis	Increased jugular venous pressure atrial fibrillation tachycardia Quiet heart sounds with a third heart sound (ventricular knock)	EKG will show: tachycardia Atrial fibrillation Low-voltage QRS complexes T wave abnormalities Doppler ultrasound shows ventricular filling abnormalities
Budd-Chiari Syndrome	Abdominal pain Diarrhea Ascites	Doppler ultrasound and CT of the abdomen shows absence of the hepatic vein filling Abdominal CT will show a rapid clearing of the caudate lobe of the liver
Splenic vein thrombosis	Signs and symptoms of: Upper abdominal pain radiating to the back Vomiting Poor bowel sounds Fever Shock Cullen's sign Grey-Turner's sign	Ultrasound of the abdomen and CT will show evidence of a splenic vein thrombosis Normal hepatic venous pressure gradient is present
Portal vein thrombosis	Symptoms depend on the underlying cause: If pancreatitis is present, the patient may develop: Upper abdominal pain radiating to the back Vomiting Poor bowel sounds fever shock Cullen's sign Grey-Turner's sign If the cause is ascending cholangitis, symptoms include: Fever rigors Right upper quadrant pain Dark urine Pale stools If abdominal sepsis is the cause, symptoms include: fever abdominal pain Signs of peritonitis	Doppler ultrasound and abdominal CT show a portal vein filling defect and absence of flow in the portal vein. MR or direct angiography show a normal hepatic venous pressure gradient.
Schistosomiasis	Patients may have a history of travel to endemic areas Constitutional symptoms such as Malaise rigors anorexia weight loss vomiting Diarrhea headache Muscular aches weakness abdominal pain urticaria fever lymphadenopathy	MR or direct angiography shows a normal hepatic venous pressure gradient
Sarcoidosis	Dry cough with dyspnea Anterior or posterior uveitis dry eyes glaucoma Skin findings may include: Maculopapular lesions on the face, back, arms and legs erythema nodosum on the legs	Chest x ray may show: hilar lymphadenopathy Upper lobe fibrosis Diffuse reticulonodular shadowing Liver biopsy shows non-necrotizing, non-caseating granulomas
Inferior vena cava obstruction	Signs and symptoms of renal cell carcinoma: Hematuria flank pain Flank or abdominal mass Weight loss hypertension	Ultrasound of the abdomen shows evidence of inferior vena cava obstruction
Nodular regenerative hyperplasia	None	Liver biopsy shows small regenerative nodules with little or no fibrosis on reticulin staining
Idiopathic portal hypertension (hepatoportal sclerosis)	None	Liver biopsy shows no evidence of cirrhosis
Vitamin A intoxication, arsenic, and vinyl chloride toxicity	None	History generally reveals exposure

References

Natural History, Complications & Prognosis

Natural History

Hepatitis Main Page
Hepatitis C
Home
Patient Info
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology & Demographics
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Differentiating Hepatitis C from other Diseases
Natural History, Complications & Prognosis
Diagnosis
History & Symptoms
Physical Examination
Lab Tests
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Hepatitis C On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis C All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis C
CDC on Hepatitis C
Hepatitis C in the news
Blogs on Hepatitis C
Directions to Hospitals Treating Hepatitis C
Risk calculators and risk factors for Hepatitis C

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [17]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Javaria Anwer M.D.[18]

Overview

The majority of individuals infected with HCV will become chronic carriers. The primary and most severe complications of HCV are hepatic, namely liver cirrhosis years after the onset of infection and the consequent development of hepatocellular carcinoma. Other classical extra-hepatic manifestations (e.g., cryoglobulinemia, lichen planus, membranoproliferative glomerulonephritis, and porphyria cutanea tarda) are also complications of chronic HCV infection. Treatment is necessary for patients with chronic stable HCV infection; otherwise, the prognosis is poor and progression of the disease is potentially fatal.

Natural History

Upon exposure, HCV causes an acute phase that is asymptomatic in approximately 80% of cases. Acute HCV persists for less than 6 months. In 15-45% of cases, HCV is an isolated acute infection with almost no chronic sequelae, even in the absence of treatment. Patients exposed to HCV will subsequently develop anti-HCV antibodies but will demonstrate undetectable viral levels and negative HCV RNA.

In the majority of cases, however, HCV persists beyond 6 months and individuals become chronic carriers of HCV. Chronic HCV occurs in approximately 55-85% of patients. These patients will have positive anti-HCV antibodies and positive nucleic acid test (NAT) for HCV RNA, demonstrating the persistence of HCV and the inability of the body to appropriately clear the infection.

Natural History of HCV - Source: http://www.who.int/en/

Complications

Hepatic Manifestations

A major complication of chronic HCV infection is cirrhosis, which ultimately leads to a decompensated state or transforms into a malignant hepatocellular carcinoma (HCC). Not all patients develop cirrhosis at the same rate; exposure to other risk factors of cirrhosis, such as alcohol, HBV, or HIV infection, or immunocompromised status may hasten fibrosis of the liver and the development of HCC.

Chronic HCV often eventually progresses to cause cirrhosis of the liver due to persistence of tissue inflammation and necrosis, along with fibrogenesis and deposition of components in the extracellular matrix. In the absence of treatment, 15-30% of patients with chronic HCV develop cirrhosis within 20 years.

Similarly, hepatocellular carcinoma (HCC) is a known complication of chronic HCV infection. Patients with HCV develop HCC when the liver reaches its cirrhotic stage. The annual risk of developing hepatocellular carcinoma in a patient with cirrhosis is approximately 2-4%.

Extrahepatic complications of HCV infection

Extrahepatic complications of HCV infection include:

• Lymphopriliferative disorders
  • Benign:Cryoglobulinemia: Divided into Type I, and mixed types; Type II, and III cryoglobulinemia. Mixed cryoglobulinemic vasculitis is usually mildly symptomatic, which include palpable purpura, arthralgia, and fatigue. Peripheral nervous system involvement demonstrating as asymmetric, painful paresthesia subsequently becoming symmetric is not uncommon. Motor deficit affecting legs in the later stages of the diseases is also seen. Rarely, the disease may progress to a life-threatening widespread vasculitis with involvement of the CNS, heart, or gastrointestinal tract.
  • Malignant: Hodgkin's lymphoma and non-Hodgkin's lymphoma
• Membranoproliferative glomerulonephritis
• Autoimmune thyroiditis
• Sjogren syndrome
• Insulin resistance and type-2 diabetes mellitus
• Porphyria cutanea tarda
• Lichen Planus
• Seronegative arthritis
• Cognitive dysfunction
• Depression
• Autoimmune hemolytic anemia (AIHA)
• immune thrombocytopenia
• Monoclonal gammopathy of undetermined significance (MGUS)

Prognosis

Acute HCV Infection

• Spontaneous clearance of HCV RNA: 15-45%
• Progression to chronic infection: 55-85%
• Fulminant hepatitis: Rare

Chronic HCV Infection

• Cirrhosis after 20 years: 10-20%
• Decompensated cirrhosis: 50% survival rate at 5 years
• Hepatocellular carcinoma: 1-4% per year

References

Diagnosis

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Treatment

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Screening

Causes

Diagnosis

History & Symptoms | Physical Examination | Lab Tests | Electrocardiogram | Chest X Ray | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention

Special Population

Children | HIV Co-infection | Kidney Disease | Treatment of African Americans | Cirrhosis Patients | Liver Transplantation Patients | Pregnancy

Resources

• CDC's Hepatitis C Fact Sheet
• CDC's Hepatitis C Frequently Asked Questions
• Hepatitis C Fact Sheet
• Hepatitis C Fact Sheet

References