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Chronic liver disease, often referred to as cirrhosis, has many etiologies. In the United States, non-alcoholic fatty liver disease (commonly associated with metabolic syndrome) is the most common cause of cirrhosis, followed by alcohol abuse.[1] Hepatitis and other viral infections, autoimmune disorders, toxic exposures, and parasitic infections may also lead to the development of cirrhosis.[2]
Hepatitis C is an acute or chronic infection caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation. The infection ranges in severity from a mild illness that lasts a few weeks to a serious, lifelong illness.[3]
Hepatitis C is an underrecognized, underdiagnosed disease with an increasing prevalence worldwide. Globally, an estimated 130-150 million people have chronic hepatitis C, of whom a significant number will develop cirrhosis or liver cancer, and another 700,000 will die from HCV infection–related liver diseases.[3]
In the United States, about 2.7-3.9 million people currently have chronic HCV infection[4]—with "baby boomers" (those born between 1946 and 1965) representing about 75% of the infected adult population.[5]
The image shows a hypothesis for HCV-induced fibrosis/cirrhosis and hepatocellular carcinoma (HCC) in a chronically infected liver. EMT = epithelial mesenchymal transition; TGF-β = transforming growth factor-β; TISCs = tumor initiating stem-like cells.
Image courtesy of Kwon YC, Ray RB, Ray R. EXCLI J. 2014;13:977-96. [Open access.] PMID: 26417315, PMCID: PMC4464452.
HCV is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family (genus Hepacivirus).[6] HCV primarily targets hepatocytes[7,8] and, possibly, B lymphocytes.[7] Strong virus-specific cytotoxic T lymphocyte and helper T cell responses aid in viral clearance.[7,8] However, the virus can produce a daily minimum of 10 trillion new viral particles and has an average 6-7–week incubation period.[9]
On the basis of homology in HCV genomic analysis, scientists have identified at least seven distinct HCV genotypes and over 67 subtypes whose distribution varies throughout the world.[6] Genotype 1 is the predominant HCV infection in the United States and worldwide[4,6]; it is found in nearly 75% of all US HCV infections.[4] Interestingly, HCV is closely related to hepatitis G, dengue, and yellow fever viruses, which also have a presence in the Americas.[9]
The confocal fluorescence microscopy image (left) shows a model of the HCV assembly process. An electroporated hepatocyte with the HCV genome shows the accumulation of NS2 (red) and core protein (blue) in close proximity to cytoplasmic lipid droplets (green), the putative site of HCV assembly. The nucleus was counterstained with DAPI (4′,6-diamidino-2-phenylindole) (gray). The electron micrograph (right) depicts HCV itself.
Images courtesy of (1) Popescu CI, Rouille Y, Dubuisson J. Viruses. 2011;3(11):2238-54. [Open access.] PMID: 22163343, PMCID: PMC3230850 (left); and (2) Maria Teresa Catanese, Martina Kopp, Kunihiro Uryu , and Charles Rice via Wikimedia Commons/Tim Vickers (right).
RNA-dependent RNA polymerase, a critical enzyme in HCV replication, lacks proofreading capabilities, thereby generating a large number of mutant viruses known as quasispecies[10] that represent minor molecular variations with only a 1%-3% nucleotide heterogeneity.[6] HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical disease course as well as the difficulties in vaccine development.[6]
In most HCV-infected people (75%-85%), viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis.[8] Study findings suggest that at least 50% of hepatocytes in patients with chronic hepatitis C may be infected with HCV.[11]
Simplified diagram of HCV replication cycle courtesy of Wikimedia Commons/Graham Colm.
HCV is a blood-borne illness, transmitted primarily through direct large or repeated percutaneous exposure to infectious blood.[4] The virus can survive outside the body at room temperature for at least 16 hours but not longer than 4 days.[12]
The following are common HCV transmission sources[4,12]:
More infrequently, HCV transmission may also occur via the following means[4,12]:
The real-time sonogram was obtained in a young female patient with HCV-associated cirrhosis. Numerous well-defined, hyperechoic nodules are shown.
Image courtesy of Medscape.
At-risk individuals
Hepatitis C is a serious health concern, particularly because many infected people are unaware of their infection owing to the fact that the majority are asymptomatic until perhaps decades later.[4,5] It is the leading cause of chronic hepatitis and of liver transplantation in the United States.[13]
Individuals known to be at increased risk for HCV infection include the following[4,12]:
The Doppler sonogram was obtained in a patient with hepatitis B virus (HBV) and HCV infection. Patency of the transjugular intrahepatic portosystemic shunt (TIPS) is shown.
Image courtesy of Medscape.
HCV infections account for approximately 30,000 new infections and 15,000-20,000 deaths each year in the United States.[14] Of the newly acquired infections, an estimated 80% occur in injection drug users; less than 10% are acquired through sexual exposure; and up to 10% are due to other causes, including occupational or perinatal exposure and hemodialysis.[12]
The overall prevalence of anti-HCV antibodies in the United States is 1.0%-1.3% of the population,[12,15] with a large percentage of these individuals positive for HCV RNA, meaning that active viral replication continues to occur. As noted earlier, an estimated 2.7-3.9 million people in the United States are infected with HCV, with a significant proportion having chronic infection.[4,5] Genotype 1a occurs in 57%-58% of US patients; genotype 1b occurs in 17%-21%.[12]
Worldwide, the average viremic rate is 67% and varies among regions (eg, 48.7% in Central Asia [5.8% anti-HCV prevalence] to 80.2% in Tropical Latin America [1.6% anti-HCV prevalence]).[15] Although 49.1% of all adult anti-HCV infections globally are caused by genotype 1, those belonging to genotypes 3 (17.9%), 4 (16.8%), and 2 (11.0%) comprise the majority of the remainder. High prevalence rates of genotype 4 (93.1%) (particularly subtype 4a) in Egypt have been attributed to the use of contaminated parenteral antischistosomal therapy.[15]
Adapted image courtesy of Messina JP, Humphreys I, Flaxman A, et al. Hepatology. 2015;61(1):77-87. [Open access.] PMID: 25069599, PMCID: PMC4303918. The size of pie charts is proportional to the number of seroprevalent cases as estimated by Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Hepatology. 2013;57(4):1333-42. PMID: 23172780.
HCV was largely responsible for the increase in the incidence of HCC in the United States during the final decades of the 20th century,[16] and it remains a leading cause of HCC.[13] In the United States, the number of deaths due to HCV-related complications increased from over 16,600 in 2010 to just under 19,370 in 2013. These numbers are anticipated to be even higher in future due to a current large pool of undiagnosed patients with chronic infection (the baby boomer population).[5,14]
The contrast-enhanced abdominal CT scan was obtained from a patient with HCV who avoided follow-up until HCC developed. The CT scan reveals a mixed hypo-isodense lesion with regular borders, as well as enlarged lymph nodes (about 1.5 cm) at the hepatic hilum.
Image courtesy of Strazzulla A, Matera G, Mammone SV, et al. BMC Infect Dis. 2014;14 suppl 5:S7. [Open access.] PMID: 25236848, PMCID: PMC4160901.
About 70%-80% of HCV-infected people are asymptomatic, even in the presence of acute infection.[17] The initial symptoms of the disease are often extrahepatic and may involve the joints, muscle, and skin, including the following[4,18]:
Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension, such as mental status changes from hepatic encephalopathy, ankle edema and abdominal distention from ascites, and/or hematemesis or melena from variceal bleeding.[18]
The sonogram was obtained from a patient with advanced cirrhosis. Note the nodularity of the liver, which is echogenic in comparison to the renal parenchyma (R), and the presence of ascites.
Image courtesy of Medscape.
In general, physical findings are normal until portal hypertension or decompensated liver disease develops. Signs of decompensated liver disease may involve the head, hand, and skin, including the following[18]:
Other common extrahepatic manifestations include the following[18]:
Images courtesy of Khattab MA, Eslam M, Alavian SM. Hepat Mon. 2010;10(4):258-69. [Open access.] PMID: 22312391, PMCID: PMC3271318.
Acute hepatitis is a short-term illness that occurs within the first 6 months after exposure to HCV.[13]
Chronic hepatitis is a long-term illness that develops over years and may lead to serious liver disease, including cirrhosis and liver cancer. An estimated 75%-85% of people with acute infection will develop the chronic form of the illness.[8]
Adapted image courtesy of Aman W, Mousa S, Shiha G, Mousa SA. Virol J. 2012;9:57. [Open access.] PMID: 22385500, PMCID: PMC3325870. Data source: Centers for Disease Control and Prevention (CDC).[4]
Hepatitis C spontaneously clears in only 15%-25% of infected persons.[4] Of the 75%-85% with chronic infection, up to 20% will develop cirrhosis within 20 years of disease onset.[4] If chronic hepatitis C infection arises early in life, the consequences tend to be less severe.[20,21] However, HBV coinfection, iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis and, potentially, to HCC.[22,23]
About 20% of chronically infected patients will have decompensated cirrhosis, and about 10% develop HCC.[24] The risk of cirrhosis and HCC doubles in patients who acquired HCV infection via transfusion.[25]
In 2014, chronic liver disease and cirrhosis was the 12th leading cause of death in the United States.[26]
Image courtesy of Wikimedia Commons/Bruce Blaus.
Early diagnosis of HCV infection is rare owing to the majority of patients being asymptomatic.[3,4] Thus, unfortunately, the infection may remain undiagnosed, often until serious liver damage has developed.
HCV infection is diagnosed in two steps.[3,9] Screening for anti-HCV antibodies with a serologic test identifies people who have been infected with the virus. If the test is positive for anti-HCV antibodies, a nucleic acid test for HCV RNA is used to confirm chronic HCV infection, because a small minority will spontaneously clear the infection by a strong immune response without the need for treatment. Although no longer infected, these individuals will still test positive for anti-HCV antibodies.
In addition to the at-risk individuals discussed in slide 5, the CDC recommends hepatitis C testing for anyone with abnormal liver test results or liver disease.[4]
Image courtesy of Wikimedia Commons/Graham Colm.
Once the diagnosis of hepatitis C has been confirmed, assess the patient's degree of liver damage (fibrosis and cirrhosis).[4] A variety of noninvasive tests and/or liver biopsy may be used for this purpose, depending on the level of disease. In addition, if possible, identify the genotype of the HCV strain, as this will help determine the optimal treatment options.
The degree of liver damage and virus genotype are used to guide treatment decisions and management of the disease. Furthermore, it is possible for a person to be infected with more than one genotype.[4] Early diagnosis may prevent HCV-related health problems from arising and potentially prevent transmission of the virus.
The image depicts two representative agarose gels of polymerase chain reaction (PCR) products demonstrating different HCV genotypes. On both gels, lanes 1 and 6, plus lanes 11 (A) or 12 (B) are 100 bp DNA size markers; lanes 2, 3, and 5 are positive controls for, respectively, genotype 1a (338 bp), genotype 2 (286 bp), and genotype 3a (227 bp).
On gel A, lanes 7 and 8 are two sets of PCR amplifications for one patient, positive for genotype 3a. Lanes 9 and 10 are two sets of PCR amplifications for another patient, positive for genotype 1a. On gel B, lanes 7 and 8 are two sets of PCR amplifications for a single patient resulting in genotype 1a. Lane 9 is an empty well; lane 10 is positive for genotype 2; and lane 11 is positive for genotype 1b.
Adapted image courtesy of Zarkesh-Esfahani SH, Kardi MT, Edalati M. Virol J. 2010;7:69. [Open access.] PMID: 20331907, PMCID: PMC2852391.
Hepatitis C does not always require treatment, as the immune response in some people will clear the infection.[3] However, as needed, newer hepatitis C drugs are able to treat the chronic liver disease without the serious side effects of previous medications.[3]
The goal of hepatitis C treatment is virologic cure.[3,9,27] Factors that affect cure rate include the strain of the virus; patient features, including race, age, disease severity, and comorbidities; and treatment type.[3,9] Careful screening is necessary before initiating therapy to determine the most appropriate approach for each individual patient.
Adapted image courtesy of Uhl P, Fricker G, Haberkorn U, Mier W. Int J Mol Sci. 2014;15(5):7500-12. [Open access.] PMID: 24786290, PMCID: PMC4057686.
The treatment of hepatitis C has evolved over time. Initial studies used interferon (IFN) monotherapy.[28] Subsequently, combination therapy was used with ribavirin (RBV) and IFN, or with IFN and the addition of polyethylene glycol (PEG) molecules (ie, PEG-IFN).
Protease inhibitors have emerged as a third feature of combination therapy. Boceprevir was the first protease inhibitor indicated for use in HCV infection, approved by the US Food and Drug Administration (FDA) in 2011, which was followed in the same year by the approval of telaprevir.[29] However, these two protease inhibitors are not currently recommended due to the more recent availability of more effective options. A third protease inhibitor, simeprevir, was approved in 2013; this agent is currently recommended as a part of combination therapy for chronic hepatitis C.[30]
Since 2013, the introduction of non-IFN or RBV treatment has significantly transformed ongoing management. Combination medications such as ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, sofosbuvir/velpatasvir, and others have provided pill-based treatments without the level of side effects seen in the previous IFN-based therapies.
In Australia, current HCV treatment options include several medications not yet FDA approved in the United States.[31]
Image courtesy of Rossi LM, Escobar-Gutierrez A, Rahal P. Viruses. 2015;7(3):1153-88. [Open access.] PMID: 25781918, PMCID: PMC4379565.
Direct-acting antiviral agents
As noted, scientific advances have led to the development of new antiviral drugs for hepatitis C that are much more effective, safe, and better-tolerated than previously existing treatment options.[3] These oral direct-acting antiviral agent (DAA) therapies simplify hepatitis C management by significantly decreasing the monitoring requirements and by increasing cure rates.[31] Although the associated treatment costs remain quite high and have limited availability in some global settings,[3] the efficacy and compliance related to the use of these medications has been very positive.[32]
Ongoing efforts to ensure that these advances lead to greater access to treatment globally remain a focus for the World Health Organization (WHO) and other groups.[3]
Adapted table courtesy of Chae HB, Park SM, Youn SJ. ScientificWorldJournal. 2013;2013:704912. [Open access.] PMID: 23844410, PMCID: PMC3687480.
No vaccine exists for hepatitis C, therefore prevention of HCV infection relies on reducing the risk of viral exposure in at-risk groups and settings, as well as increasing general HCV screening.[3]
Examples of primary prevention interventions recommended by WHO are as follows[3]:
For HCV-infected individuals, WHO recommendations include the following secondary and tertiary prevention methods[3]:
Image courtesy of the CDC.
Hepatitis C is an underrecognized and underdiagnosed disease with an increasing global prevalence. Early screening and diagnosis in at-risk populations is essential—but often overlooked.
Novel antiviral therapies for hepatitis C have the potential to significantly reduce the prevalence of HCV infection. Eliminating HCV as a disease within the United States is a future possibility with the use of DAAs in combination with targeted behavioral interventions to reduce transmission events.
The MRI (left) illustrates a region of interest at the level of the porta hepatis in the liver of an elderly patient with chronic hepatitis C. Histologic examination of the liver biopsy specimen (right) revealed stage 4 hepatic fibrosis and grade 2 necroinflammatory activity (hematoxylin-eosin [HE] stain; original magnification, ×50).
Images courtesy of Wu Z, Matsui O, Kitao A, et al. PLoS One. 2015;10(3):e0118297. [Open access.] PMID: 25742285, PMCID: PMC4351185.
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