Discovery of Hepatitis C Virus

**3**

**Chapter 1**

Medicine 2020

*Talari Praveen*

research around it.

**1. Introduction**

Antigen antibody reaction

000 deaths annually [4].

**2. Discovery of hepatitis A and B**

**Abstract**

Discovery of Hepatitis C Virus:

Nobel Prize in Physiology and

Scientists were successful in discovering Hepatitis A and B, but there is another virus which has a long incubation period, many people are asymptomatic and cause adverse effects. Three scientists Harvey J Alter, Michael Houghton and Charles M Rice who have contributed their work in discovering a non-A, non-B hepatitis virus called Hepatitis C. Hepatitis is a disorder associated with the functioning hepatic cells in the liver. The person infected with Hepatitis C will have poor functioning of liver, vomiting, fatigue, jaundice and appetite. In this paper, I am going to explain about the Hepatitis C virus, and the work was done by three scientists and various

**Keywords:** Hepatitis C, Post-transfusion, non-A non-B hepatitis, Gene expression,

Hepatitis C virus is a blood-borne pathogen. The person infected with this virus has defects in the functioning of the liver and blood. The progress of the virus in the human body is slow acting. The incubation period varies from person to person, it is about 2–3 months [1]. Hepatitis C is associated with chronic hepatitis which means inflammation of the liver and may also lead to liver failure sometimes cancer called Hepatocellular carcinoma [2]. According to the World Health Organization, it was estimated that there are about 70 million of the total world population infected with the Hepatitis C virus [3, 4]. If the treatment is delayed, the disease will progress and cause liver cirrhosis and hepatocellular carcinoma [5]. Hepatitis C is causing 400

In 400 B.C., Hippocrates called hepatitis infection as 'Epidemic Jaundice' and told that "The bile contained in the liver is full of phlegm and blood, and erupts.. Such an eruption, the patient soon raves, becomes angry, talks nonsense and barks like a dog" [6]. During the second world war, the infection to the liver was thought of infection by several viruses and called it 'Viral Hepatitis'. After that, in 1947,

#### **Chapter 1**

## Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020

*Talari Praveen*

#### **Abstract**

Scientists were successful in discovering Hepatitis A and B, but there is another virus which has a long incubation period, many people are asymptomatic and cause adverse effects. Three scientists Harvey J Alter, Michael Houghton and Charles M Rice who have contributed their work in discovering a non-A, non-B hepatitis virus called Hepatitis C. Hepatitis is a disorder associated with the functioning hepatic cells in the liver. The person infected with Hepatitis C will have poor functioning of liver, vomiting, fatigue, jaundice and appetite. In this paper, I am going to explain about the Hepatitis C virus, and the work was done by three scientists and various research around it.

**Keywords:** Hepatitis C, Post-transfusion, non-A non-B hepatitis, Gene expression, Antigen antibody reaction

#### **1. Introduction**

Hepatitis C virus is a blood-borne pathogen. The person infected with this virus has defects in the functioning of the liver and blood. The progress of the virus in the human body is slow acting. The incubation period varies from person to person, it is about 2–3 months [1]. Hepatitis C is associated with chronic hepatitis which means inflammation of the liver and may also lead to liver failure sometimes cancer called Hepatocellular carcinoma [2]. According to the World Health Organization, it was estimated that there are about 70 million of the total world population infected with the Hepatitis C virus [3, 4]. If the treatment is delayed, the disease will progress and cause liver cirrhosis and hepatocellular carcinoma [5]. Hepatitis C is causing 400 000 deaths annually [4].

#### **2. Discovery of hepatitis A and B**

In 400 B.C., Hippocrates called hepatitis infection as 'Epidemic Jaundice' and told that "The bile contained in the liver is full of phlegm and blood, and erupts.. Such an eruption, the patient soon raves, becomes angry, talks nonsense and barks like a dog" [6]. During the second world war, the infection to the liver was thought of infection by several viruses and called it 'Viral Hepatitis'. After that, in 1947,

British hepatologist F.O. MacCallum has classified viral hepatitis into Hepatitis A which is Epidemic hepatitis and Hepatitis B which is serum hepatitis [7].

Baruch Blumberg (1925–2011) was a geneticist at National Institute of Health in Bethesda who is working on human disease susceptibility. He collected blood samples of people from many places in the world to study inherited diseases and susceptibility [7]. He found an unfamiliar reaction taking place in the serum of a hemophilic patient who needs blood and an Australian aborigine who is a donor. He initially thought that he discovered a new lipoprotein. After that, in the serum of a hemophilic patient, he could find detection of a new antigen, he called that as 'Australian-antigen' [7, 8]. In 1967, Blumberg linked the Australian-antigen with viral hepatitis, and in 1968, Alfred Price used Immuno-electrophoretic technique to explain that serum antigen that Blumberg discovered was related to hepatitis and called it as Serum hepatitis antigen. Later, both Australianantigen and Serum hepatitis antigen were confirmed that these are viral particles. Blumberg performed several serological tests using chimpanzees to confirm the antigens are of Hepatitis B virus. In 1976, Blumberg got Nobel Prize Physiology and Medicine [9]. At that time, it was impossible to identify who are carriers of diseases and who are healthy donors, the effect of disease on a person is silent and progressive [4].

#### **3. Discovery of hepatitis C**

#### **3.1 Harvey J Alter**

Along with Blumberg, there is another person who also contributed his work in discovering Hepatitis B is Harvey J Alter. Alter also worked at National Institute of Health in Bethesda [10]. In the 1970s, people started studying the relationship between blood donors infected with Hepatitis B and post-transfusion hepatitis [8]. While they were studying about this, Alter found out that, though Hepatitis B positive donors prevented from donating blood, he found that blood transfused people were still infected with other 'Hepatitis related infections' [11]. Alter came across a patient who had a mild form of the disease and later that patient had Hepatitis associated diseases after a long incubation period. Based on this, he proposed that there may be two different viruses causing 'post-transfusion hepatitis' [11]. In 1975, Feinstone, Purcell and other scientists tested patients who are non-B hepatitis and found that Hepatitis A is not causing the disorders [12, 13].

The blood transfusion of non-B hepatitis was spreading to more numbers of people. They were sure the infection was not because of Hepatitis A or B, then came up with a term called 'non-A, non-B hepatitis' (NANBH) [12, 13]. Alter and his colleagues were clear that NANBH is responsible for post-transfusion hepatitis, but they were unable to show what NANBH is? Since there is no tool to diagnose NANBH, many people got affected by blood transfusion. The only animal model which is susceptible to NANBH is chimpanzees, Tabor et al. [14] have infected chimpanzees to study the hepatocyte infection and agents causing the disease. They have taken plasma from NANBH people and infected chimpanzees, and they found cirrhosis and hepatocellular carcinoma disorders in animal [4]. After several experiments, Alter and his colleagues found that NANBH has essential lipids which are enveloped around the virus which are different from Hepatitis B [15, 16]. Alter did not give conclusive results to state the causative agent is causing post-transfusion hepatitis.

**5**

**Figure 1.**

*Summary of Houghton work.*

*Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020*

λ

In 1982, Houghton worked at Chiron Corporation and came up with molecular methods called cDNA library. Houghton and his colleagues infected chimpanzees with NANDH virus and have taken plasma from them, that plasma they have centrifuged to get a pellet of virus and they have extracted the nucleic acid from it. They have denatured the nucleic acid because they do not know whether it is DNA or RNA. After denature, they synthesized the cDNA [17]. They transduced the cDNA to a bacterial

bacterial vector undergoes translation to display cDNA-encoded polypeptides. They also looked for whether similar antigen that is expressed in the serum of NANBH patients by using screening techniques. If an antigen is found in the body, the immune system will generate antibodies against it. They have considered those patients as sources of viral antibodies, they have taken plasma by centrifuging blood of NANBH patients [18]. The bacterial vector has expressed the cDNA proteins, and by introducing plasma of the patient to the bacterial colony, the antibodies in the plasma will bind

to polypeptides of bacteria [4]. Based on this idea of Molecular Biology and

Immunology, they performed several screenings of the above experiment about <sup>6</sup> 10 and found there is one colony that did not match human or chimpanzee DNA

sequence, it matched with the sequence of a virus family called Flaviviridae [4]. They named it as cDNA clone 5–1-1 and named it as Hepatitis C virus (**Figure 1**) [17– 20]. Houghton and his colleagues have immediately taken this knowledge further. They have collected suspected blood samples from Alter and performed the above experiment on those samples. They found all the blood samples they have tested are positive Hepatitis C. Using this diagnostic technique, donors were tested blood samples before transfusion which decreased the number of hepatitis cases [4]. But, Houghton has not evidently proved that Hepatitis C is only the causative agent or a

To find out what is actually causing chronic liver cirrhosis, two scientists Kunitada Shimontohno and Charles Rice came up with a new experiment. Blight and Rice [21], they have sequenced the viral genome and found that it is positive RNA strand about 96000 nucleotides, the RNA undergoes direct translation to form proteins, the primary transcription process is eliminated. The viral genome is a long

gt11 strain, the method is called transduction [18]. The

*DOI: http://dx.doi.org/10.5772/intechopen.96734*

**3.2 Michael Houghton**

vector using a bacteriophage

mix of viruses causing disorder?

**3.3 Charles M Rice**

#### **3.2 Michael Houghton**

*Advances in Hepatology*

progressive [4].

**3.1 Harvey J Alter**

**3. Discovery of hepatitis C**

British hepatologist F.O. MacCallum has classified viral hepatitis into Hepatitis A

Baruch Blumberg (1925–2011) was a geneticist at National Institute of Health in Bethesda who is working on human disease susceptibility. He collected blood samples of people from many places in the world to study inherited diseases and susceptibility [7]. He found an unfamiliar reaction taking place in the serum of a hemophilic patient who needs blood and an Australian aborigine who is a donor. He initially thought that he discovered a new lipoprotein. After that, in the serum of a hemophilic patient, he could find detection of a new antigen, he called that as 'Australian-antigen' [7, 8]. In 1967, Blumberg linked the Australian-antigen with viral hepatitis, and in 1968, Alfred Price used Immuno-electrophoretic technique to explain that serum antigen that Blumberg discovered was related to hepatitis and called it as Serum hepatitis antigen. Later, both Australianantigen and Serum hepatitis antigen were confirmed that these are viral particles. Blumberg performed several serological tests using chimpanzees to confirm the antigens are of Hepatitis B virus. In 1976, Blumberg got Nobel Prize Physiology and Medicine [9]. At that time, it was impossible to identify who are carriers of diseases and who are healthy donors, the effect of disease on a person is silent and

Along with Blumberg, there is another person who also contributed his work in discovering Hepatitis B is Harvey J Alter. Alter also worked at National Institute of Health in Bethesda [10]. In the 1970s, people started studying the relationship between blood donors infected with Hepatitis B and post-transfusion hepatitis [8]. While they were studying about this, Alter found out that, though Hepatitis B positive donors prevented from donating blood, he found that blood transfused people were still infected with other 'Hepatitis related infections' [11]. Alter came across a patient who had a mild form of the disease and later that patient had Hepatitis associated diseases after a long incubation period. Based on this, he proposed that there may be two different viruses causing 'post-transfusion hepatitis' [11]. In 1975, Feinstone, Purcell and other scientists tested patients who are non-B hepatitis and

The blood transfusion of non-B hepatitis was spreading to more numbers of people. They were sure the infection was not because of Hepatitis A or B, then came up with a term called 'non-A, non-B hepatitis' (NANBH) [12, 13]. Alter and his colleagues were clear that NANBH is responsible for post-transfusion hepatitis, but they were unable to show what NANBH is? Since there is no tool to diagnose NANBH, many people got affected by blood transfusion. The only animal model which is susceptible to NANBH is chimpanzees, Tabor et al. [14] have infected chimpanzees to study the hepatocyte infection and agents causing the disease. They have taken plasma from NANBH people and infected chimpanzees, and they found cirrhosis and hepatocellular carcinoma disorders in animal [4]. After several experiments, Alter and his colleagues found that NANBH has essential lipids which are enveloped around the virus which are different from Hepatitis B [15, 16]. Alter did not give conclusive results to state the causative

found that Hepatitis A is not causing the disorders [12, 13].

agent is causing post-transfusion hepatitis.

which is Epidemic hepatitis and Hepatitis B which is serum hepatitis [7].

**4**

In 1982, Houghton worked at Chiron Corporation and came up with molecular methods called cDNA library. Houghton and his colleagues infected chimpanzees with NANDH virus and have taken plasma from them, that plasma they have centrifuged to get a pellet of virus and they have extracted the nucleic acid from it. They have denatured the nucleic acid because they do not know whether it is DNA or RNA. After denature, they synthesized the cDNA [17]. They transduced the cDNA to a bacterial vector using a bacteriophage λ gt11 strain, the method is called transduction [18]. The bacterial vector undergoes translation to display cDNA-encoded polypeptides. They also looked for whether similar antigen that is expressed in the serum of NANBH patients by using screening techniques. If an antigen is found in the body, the immune system will generate antibodies against it. They have considered those patients as sources of viral antibodies, they have taken plasma by centrifuging blood of NANBH patients [18]. The bacterial vector has expressed the cDNA proteins, and by introducing plasma of the patient to the bacterial colony, the antibodies in the plasma will bind to polypeptides of bacteria [4]. Based on this idea of Molecular Biology and Immunology, they performed several screenings of the above experiment about <sup>6</sup> 10 and found there is one colony that did not match human or chimpanzee DNA sequence, it matched with the sequence of a virus family called Flaviviridae [4]. They named it as cDNA clone 5–1-1 and named it as Hepatitis C virus (**Figure 1**) [17– 20].

Houghton and his colleagues have immediately taken this knowledge further. They have collected suspected blood samples from Alter and performed the above experiment on those samples. They found all the blood samples they have tested are positive Hepatitis C. Using this diagnostic technique, donors were tested blood samples before transfusion which decreased the number of hepatitis cases [4]. But, Houghton has not evidently proved that Hepatitis C is only the causative agent or a mix of viruses causing disorder?

#### **3.3 Charles M Rice**

To find out what is actually causing chronic liver cirrhosis, two scientists Kunitada Shimontohno and Charles Rice came up with a new experiment. Blight and Rice [21], they have sequenced the viral genome and found that it is positive RNA strand about 96000 nucleotides, the RNA undergoes direct translation to form proteins, the primary transcription process is eliminated. The viral genome is a long

**Figure 1.** *Summary of Houghton work.*

open reading frame (ORF), different types of proteins are translated from one ORF which has several translation initiation and termination codons [21].

They have found that there is a non-coding region at the 3'and 5′ ends of the viral RNA genome which is responsible for replication of the virus [21, 22]. Kolykhalov et al. [23] have constructed a viral genome which has conserved 3′ region at 5′ nontranslated region (5' NTR) and rest in long ORF (**Figure 2**). That genome gene they have injected to the chimpanzee liver to check the viral replication, but unfortunately the experiment failed, they did not find new viruses in the blood. While finding reasons for failure of experiment, they came across that during replication, mutations are common in the viral genome. To eliminate the mutations, they have engineered a few new sequences with silent markers. With all new sequences, they have created a new repaired conserved 3′ region (**Figure 3**) [4, 23, 24]. They repeated the above experiment with a newly engineered genome and the experiment worked resulting in chimpanzees having liver cirrhosis and hepatocellular carcinoma. Based on this, Rice gave the conclusion that only Hepatitis C virus alone causes hepatitis, there no other causative agent involved.

#### **Figure 2.**

*Viral genome with conserved 3' region.*


#### **Figure 3.**

*Repaired conserved 3' region Genomes [23].*

#### **4. Mode of infection and diseases**


**7**

**Figure 5.**

*Viral genome expression [5].*

**Figure 4.**

*Structure of hepatitis C .*

*Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020*

**Structure of Virus:** Hepatitis C is a single-stranded RNA virus belonging to the family of Flaviviridae and there are seven genotypes (gt 1–7) and 67 subtypes which states genetic diversity is high [5]. The size of the virus is about 56–65 nm in diameter and the viral core about 45 nm. In the viral envelope, there are viral spikes which are formed by E1 and E2 glycoprotein heterodimers. Viral membranes consist of several lipoproteins those are low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and apolipoproteins (Apo) which are A1, B, C (**Figure 4**) [5]. **Viral Genome:** As described above, viral genomes contain 96000 nucleotides and one ORF with the coding region of 3010 to 3033 nucleotides and 5′ and 3′ ends have non-translational (NTR) regions. The translation of viral RNA takes place in the endoplasmic reticulum of hepatic cells in the liver which is initiated by the IRES region which is adjacent to 5'NTR (**Figure 3**). The translation results in the formation of three structural proteins which are core, E1 and E2 and seven non-structural proteins which are p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B. The structural proteins form viral components and non-structural proteins regulate viral growth and

**Viral Cycle:** When a person has blood transfusion from the Hepatitis C infected person, the virus reaches to the liver cell and binds to the lipoviral receptor proteins and the whole virus is engulfed into the cell by a process called clathrinmediated endocytosis. The virus reaches the endoplasmic reticulum and releases its RNA. The ORF of RNA is translated to form structural and non-structural proteins.

*DOI: http://dx.doi.org/10.5772/intechopen.96734*

replication (**Figure 5**) [5].

**5. Molecular mechanisms of replication**

### **5. Molecular mechanisms of replication**

*Advances in Hepatology*

causative agent involved.

*Viral genome with conserved 3' region.*

**4. Mode of infection and diseases**

**Virus Type Family Genetic** 

**material**

Hepatitis B Hepadna DNA Blood transfusion Liver failure, jaundice Hepatitis C Flaviviridae RNA Blood transfusion Inflammation of liver and

Hepatitis A Picornaviridae RNA Contaminated food

**Disorders Disorders**

Abdominal pain, nausea,

hepatocellular carcinoma

fatigue

and water

*Repaired conserved 3' region Genomes [23].*

open reading frame (ORF), different types of proteins are translated from one ORF

They have found that there is a non-coding region at the 3'and 5′ ends of the viral RNA genome which is responsible for replication of the virus [21, 22]. Kolykhalov et al. [23] have constructed a viral genome which has conserved 3′ region at 5′ nontranslated region (5' NTR) and rest in long ORF (**Figure 2**). That genome gene they have injected to the chimpanzee liver to check the viral replication, but unfortunately the experiment failed, they did not find new viruses in the blood. While finding reasons for failure of experiment, they came across that during replication, mutations are common in the viral genome. To eliminate the mutations, they have engineered a few new sequences with silent markers. With all new sequences, they have created a new repaired conserved 3′ region (**Figure 3**) [4, 23, 24]. They repeated the above experiment with a newly engineered genome and the experiment worked resulting in chimpanzees having liver cirrhosis and hepatocellular carcinoma. Based on this, Rice gave the conclusion that only Hepatitis C virus alone causes hepatitis, there no other

which has several translation initiation and termination codons [21].

**6**

**Figure 3.**

**Figure 2.**

**Structure of Virus:** Hepatitis C is a single-stranded RNA virus belonging to the family of Flaviviridae and there are seven genotypes (gt 1–7) and 67 subtypes which states genetic diversity is high [5]. The size of the virus is about 56–65 nm in diameter and the viral core about 45 nm. In the viral envelope, there are viral spikes which are formed by E1 and E2 glycoprotein heterodimers. Viral membranes consist of several lipoproteins those are low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and apolipoproteins (Apo) which are A1, B, C (**Figure 4**) [5].

**Viral Genome:** As described above, viral genomes contain 96000 nucleotides and one ORF with the coding region of 3010 to 3033 nucleotides and 5′ and 3′ ends have non-translational (NTR) regions. The translation of viral RNA takes place in the endoplasmic reticulum of hepatic cells in the liver which is initiated by the IRES region which is adjacent to 5'NTR (**Figure 3**). The translation results in the formation of three structural proteins which are core, E1 and E2 and seven non-structural proteins which are p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B. The structural proteins form viral components and non-structural proteins regulate viral growth and replication (**Figure 5**) [5].

**Viral Cycle:** When a person has blood transfusion from the Hepatitis C infected person, the virus reaches to the liver cell and binds to the lipoviral receptor proteins and the whole virus is engulfed into the cell by a process called clathrinmediated endocytosis. The virus reaches the endoplasmic reticulum and releases its RNA. The ORF of RNA is translated to form structural and non-structural proteins.

**Figure 4.** *Structure of hepatitis C .*

**Figure 5.** *Viral genome expression [5].*

As I mentioned, the structural proteins form viral components and non-structural proteins regulate viral growth and replication using cellular components. The viral components and replicated RNA fragments reach the Golgi apparatus and unite to form mature viruses. The formed viruses enter the blood by bursting the liver cell. One single entry produces millions of viruses that cause liver dysfunction by bursting hepatic cells [5].

#### **6. Research: a way to discovery of vaccine**

Phosphatidylinositol 4-kinase IIIα (PI4KA) is a hepatic cellular protein which converts phosphatidylinositol to phosphatidylinositol 4-phosphate (PI4P) [25]. This protein has several roles in the viral replication and growth in an infected cell. PI4KA interacts with structural proteins in shaping the virus and also interaction with the non-structural protein of NS5B will accumulate the essential cellular material for viral growth [26]. When the Phosphatidylinositol 4-kinase III?? is knocked down, the replication and production of viral components are affected. Harak et al. [26] have done an in-vitro gene knockdown method to inhibit viral growth. Sarhan et al. [27] have also done similar experiments. They found other proteins called GSK3α and β interacting with viral NS5A. The GSK3α and β phosphorylates the NS5A. The phosphorylation of NS5A results in multiple functions such as viral maturation and release. If the GSK3α and β genes are knocked down, the viral maturation and release is inhibited [27].

When any foreign particles enter the body, our immune system will identify that antigen. The human immune system has B cells, T cells and Natural killer cells play essential roles in detecting antigens. Hepatitis C virus has E2 glycoprotein in the core. CD81 markers which are present on B-cells will interact with E2 glycoprotein [28]. The binding of E2 and CD81, B-cells release serum antibodies to neutralize the viral activity. Research around Molecular Biology and Immunology will increase the chances of discovering the vaccine. Research is the stepping stone to discovering new things in science.

#### **7. Diagnosis and treatment**

When Hepatitis C is infected, the majority of the people are asymptomatic. The incubation period varies from person to person. In order to detect the virus, there are diagnostic tests to be performed. There are two ways to direct the virus, one is an indirect method based on antibodies production and direct method based on viral detection. In the indirect method, a person's blood sample will be taken which consist of serum, blood and plasma. To that blood, recombinant viral proteins core, NS3 and NS4 antigen are added. Along with recombinant proteins, colloidal gold labeled protein A is added. If the antibodies bind to antigens, the recombinant protein generates reddish-purple lines. This screening test will reveal that antibodies are present. To confirm the person infected with Hepatitis C, Recombinant Immunoblot Assay (RIBA) is antibody specific test which will direct anti-hepatitis C antibodies [29]. In the direct method diagnosis, Reverse-transcriptase polymerase chain reaction (RT-PCR) is performed which directly gives confirmatory results whether the virus is present or not [29].

The current work going on Hepatitis C is discovering a vaccine. To cure Hepatitis C, there is no vaccine. If the disorder is in advanced stages, the person needs liver transplantation. If Hepatitis C is directed at early stages like at chronic hepatitis stage, there are antiviral drug treatments which cure disorder to some extent. These

**9**

**Author details**

Centre for Human Genetics, Bangalore, Karnataka, India

provided the original work is properly cited.

\*Address all correspondence to: talaripraveen2000@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Talari Praveen

*Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020*

antiviral drugs interfere with viral replication and maturation [3]. There are several classes of drugs which interfere with viral growth. The nonstructural 3/4A inhibitor drugs Boceprevir and telaprevir interfere with NS3/4 A proteins to inhibit the viral protein formation. Nonstructural 5A inhibitors like Ledipasvir, ombitasvir, daclatasvir etc., will interfere with NS5A protein which plays an important role in viral replication and assembly of viral particles. Nonstructural 5B inhibitors like sofosbuvir interfere with NS5B which synthesizes viral RNA [3]. Treating patients with antiviral drugs will inhibit viral progress in the body. These drug targets cure

Alter, Houghton, Rice and their colleagues have contributed their work to the world of science. They have come up with new molecular and immunological techniques to detect the presence of viruses. Alter and his colleagues discovered an Australian antigen and it was non-A, non-B hepatitis (NANBH). He introduced a model organism chimpanzees to study the disease post-transfusion hepatitis. Houghton and his colleagues have brought Molecular Biology and Immunology together and diagnosed NANBH and named it as Hepatitis C virus. Rice and his colleagues sequenced the viral genome and explained its properties of replication and gene expression. He discovered that alone Hepatitis C is causing Liver cirrhosis

*DOI: http://dx.doi.org/10.5772/intechopen.96734*

the disease if the disease is at an early stage.

**8. Conclusion**

and Hepatocellular carcinoma.

#### *Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020 DOI: http://dx.doi.org/10.5772/intechopen.96734*

antiviral drugs interfere with viral replication and maturation [3]. There are several classes of drugs which interfere with viral growth. The nonstructural 3/4A inhibitor drugs Boceprevir and telaprevir interfere with NS3/4 A proteins to inhibit the viral protein formation. Nonstructural 5A inhibitors like Ledipasvir, ombitasvir, daclatasvir etc., will interfere with NS5A protein which plays an important role in viral replication and assembly of viral particles. Nonstructural 5B inhibitors like sofosbuvir interfere with NS5B which synthesizes viral RNA [3]. Treating patients with antiviral drugs will inhibit viral progress in the body. These drug targets cure the disease if the disease is at an early stage.

### **8. Conclusion**

*Advances in Hepatology*

hepatic cells [5].

proteins called GSK3

**6. Research: a way to discovery of vaccine**

Phosphatidylinositol 4-kinase III

α and β

to discovering new things in science.

whether the virus is present or not [29].

**7. Diagnosis and treatment**

tions such as viral maturation and release. If the GSK3

down, the viral maturation and release is inhibited [27].

As I mentioned, the structural proteins form viral components and non-structural proteins regulate viral growth and replication using cellular components. The viral components and replicated RNA fragments reach the Golgi apparatus and unite to form mature viruses. The formed viruses enter the blood by bursting the liver cell. One single entry produces millions of viruses that cause liver dysfunction by bursting

α

converts phosphatidylinositol to phosphatidylinositol 4-phosphate (PI4P) [25]. This protein has several roles in the viral replication and growth in an infected cell. PI4KA interacts with structural proteins in shaping the virus and also interaction with the non-structural protein of NS5B will accumulate the essential cellular material for viral growth [26]. When the Phosphatidylinositol 4-kinase III?? is knocked down, the replication and production of viral components are affected. Harak et al. [26] have done an in-vitro gene knockdown method to inhibit viral growth. Sarhan et al. [27] have also done similar experiments. They found other

phosphorylates the NS5A. The phosphorylation of NS5A results in multiple func-

When any foreign particles enter the body, our immune system will identify that antigen. The human immune system has B cells, T cells and Natural killer cells play essential roles in detecting antigens. Hepatitis C virus has E2 glycoprotein in the core. CD81 markers which are present on B-cells will interact with E2 glycoprotein [28]. The binding of E2 and CD81, B-cells release serum antibodies to neutralize the viral activity. Research around Molecular Biology and Immunology will increase the chances of discovering the vaccine. Research is the stepping stone

When Hepatitis C is infected, the majority of the people are asymptomatic. The incubation period varies from person to person. In order to detect the virus, there are diagnostic tests to be performed. There are two ways to direct the virus, one is an indirect method based on antibodies production and direct method based on viral detection. In the indirect method, a person's blood sample will be taken which consist of serum, blood and plasma. To that blood, recombinant viral proteins core, NS3 and NS4 antigen are added. Along with recombinant proteins, colloidal gold labeled protein A is added. If the antibodies bind to antigens, the recombinant protein generates reddish-purple lines. This screening test will reveal that antibodies are present. To confirm the person infected with Hepatitis C, Recombinant Immunoblot Assay (RIBA) is antibody specific test which will direct anti-hepatitis C antibodies [29]. In the direct method diagnosis, Reverse-transcriptase polymerase chain reaction (RT-PCR) is performed which directly gives confirmatory results

The current work going on Hepatitis C is discovering a vaccine. To cure Hepatitis C, there is no vaccine. If the disorder is in advanced stages, the person needs liver transplantation. If Hepatitis C is directed at early stages like at chronic hepatitis stage, there are antiviral drug treatments which cure disorder to some extent. These

interacting with viral NS5A. The GSK3

α and β

(PI4KA) is a hepatic cellular protein which

α and β

genes are knocked

**8**

Alter, Houghton, Rice and their colleagues have contributed their work to the world of science. They have come up with new molecular and immunological techniques to detect the presence of viruses. Alter and his colleagues discovered an Australian antigen and it was non-A, non-B hepatitis (NANBH). He introduced a model organism chimpanzees to study the disease post-transfusion hepatitis. Houghton and his colleagues have brought Molecular Biology and Immunology together and diagnosed NANBH and named it as Hepatitis C virus. Rice and his colleagues sequenced the viral genome and explained its properties of replication and gene expression. He discovered that alone Hepatitis C is causing Liver cirrhosis and Hepatocellular carcinoma.

### **Author details**

Talari Praveen Centre for Human Genetics, Bangalore, Karnataka, India

\*Address all correspondence to: talaripraveen2000@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] D'Souza, Raymond., & Foster, Graham R. (2004). "Diagnosis and treatment of hepatitis C." Journal of the Royal Society of Medicine, 97(5), 223-225. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC1079461/.

[2] Bukh, Jens. (2016). "The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control." Journal of Hepatology, 65(1), S2-S21. https://doi.org/10.1016/j.jhep.2016.07.035.

[3] Horsley-Silva, Jennifer L., and Vargas, Hugo E. "New Therapies for Hepatitis C Virus Infection." *Gastroenterology & Hepatology*, 13(1), 22-31. https://pubmed.ncbi.nlm.nih. gov/28420944/.

[4] Nobel Prize. (2020, October 6). "Announcement of the 2020 Nobel Prize in Physiology or Medicine."[Video]. *You Tube*. https://youtu.be/BTu6uOWLKR4.

[5] Morozov, Vladimir Alexei., and Lagaye, Sylvie. (2018). "Hepatitis C virus: Morphogenesis, infection and therapy." World Journal of Hepatology, 10(2), 186-212. https://pubmed.ncbi. nlm.nih.gov/29527256/.

[6] Ginsau, M A., and Ahmed, U A. (2019) "Examination of Blood for Hepatitis B Virus (HBV) and possible Transmission by Mosquito (Aedesaegypti)." *IOSR Journal of Environmental Science, Toxicology and Food Technology (IOSR-JESTFT)*, 13(2), DOI: 10.9790/2402-1302014851.

[7] Thomas et al. (2015). "Viral Hepatitis: Past and Future of HBV and HDV." *Cold Spring Harbor Perspectives in Medicine*, 5(2), 1-11. https://pubmed. ncbi.nlm.nih.gov/25646383/.

[8] Gerlich, Wolfram H. (2013). "Medical Virology of Hepatitis B: how it began and where we are now." Virology Journal, 10(1), 239. http://www. virologyj.com/content/10/1/23.

[9] Pilcher, Carl B. (2015). "Explorer, Nobel Laureate, Astrobiologist: Things You Never Knew about Barry Blumberg." Astrobiology, 15(1), 1-14. https://doi.org/10.1089/ast.2013.1401.

[10] Palese, Peter. (2016). "Profile of Charles M. Rice, Ralf F. W. Bartenschlager, and Michael J. Sofia, 2016 Lasker-DeBakey Clinical Medical Research Awardees." *Proceedings of the National Academy of Sciences*, 113(49), 13934-13937. https://doi.org/10.1073/ pnas.1616592113.

[11] Alter et al. (1972). "Posttransfusion Hepatitis After Exclusion of Commercial and Hepatitis-B Antigen-Positive Donors". *Annals of Internal Medicine*, 77(5), 691-699. https:// pubmed.ncbi.nlm.nih.gov/4628213/.

[12] Alter et al. (1975a). "CLINICAL AND SEROLOGICAL ANALYSIS OF TRANSFUSION-ASSOCIATED HEPATITIS." *The Lancet*, 306(7940), 838-841. https://doi.org/10.1016/ S0140-6736(75)90234-2.

[13] Alter et al. (1975b). "The emerging pattern of post-transfusion hepatitis." *The American Journal of the Medical Sciences*, 270(2), 329-334. https:// pubmed.ncbi.nlm.nih.gov/1235474/.

[14] Tabor et al. (1978). "TRANS-MISSION OF NON-A, NON-B HEPATITIS FROM MAN TO CHIMPANZEE." *The Lancet*, 311(8062), 463-466. https://doi.org/10.1016/ S0140-6736(78)90132-0.

[15] Feinstone et al. (1983). "Inactivation of Hepatitis B Virus and Non-A, Non-B Hepatitis by Chloroform." *Infection and Immunity*, 41(2), 816-821. https://iai. asm.org/content/41/2/816.

**11**

70/5/3307.

*Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020*

culture from a cloned viral genome." *Nature Medicine*, 11(7), 791-796. https://

[25] Ilboudo et al. (2014). "Overexpression of phosphatidylinositol 4-kinase type III?? is associated with undifferentiated status and poor prognosis of human hepatocellular carcinoma." *BMC Cancer*, 14(7), 1-8. https://doi.org/10.1186/1471-2407-14-7.

[26] Harak et al. (2016). "Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture." *Nature Microbiology*, 2, 1-13.

[27] Sarhan et al. (2017). "Glycogen synthase kinase 3?? inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism." *Scientific Reports*, 7(1), 1-12. https://doi.org/10.1038/s41598-017-

[28] Rosa et al. (2005). "Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C

disorders." *PANS*, 102(5), 18544-18549.

[29] Li, Hui-Chun., and Lo, Shih-Yen. (2015). "Hepatitis C virus: Virology, diagnosis and treatment." World Journal of Hepatology, 7(10), 1377. https:// www.ncbi.nlm.nih.gov/pmc/articles/

virus-associated B lymphocyte

https://doi.org/10.1073/ pnas.0509402102.

PMC4450201/.

https://doi.org/10.1038/ nmicrobiol.2016.247.

02648-6.

doi.org/10.1038/nm1268.

*DOI: http://dx.doi.org/10.5772/intechopen.96734*

[16] He et al. (1987). "Determining the Size of Non-A, Non-B Hepatitis Virus by Filtration." *Journal of Infectious Diseases*, 156(4), 636-640. https://pubmed.ncbi.

nlm.nih.gov/3114389/.

[17] Houghton, Michael. (2019 ) "Hepatitis C Virus: 30 Years after Its Discovery." *Cold Spring Harb Perspect Med*, 9(12):a037069, 1-9. https:// pubmed.ncbi.nlm.nih.gov/31501269/

[18] Choo et al. (1989). "Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome." *Science*, 244(4902), 359-362. https:// pubmed.ncbi.nlm.nih.gov/2523562/.

[19] Alter, Harvey J., Houghton, Michael.,and Rice, Charles M. "Press release: The Nobel Prize in Physiology or Medicine 2020." *The Nobel Prize*. https://www.nobelprize.org/prizes/ medicine/2020/press-release/.

[20] Houghton, Michael. (2009). "Discovery of the hepatitis C virus." Liver International, 29(s1), 82-88. https://doi.org/10.1111/j.1478-

(1997). "Secondary Structure Determination of the Conserved 98-Base Sequence at the 39 Terminus of Hepatitis C Virus Genome RNA." Journal of Virology. 71(10), 7345-7352. https://jvi.asm.org/content/71/10/7345.

[23] Kolykhalov et al. (1997). "Transmission of Hepatitis C by Intrahepatic Inoculation with

content/277/5325/570.

[21] Blight, Keril J., and Rice, Charles M.

[22] Tanka et al. (1996). "Structure of the 39 Terminus of the Hepatitis C Virus Genome." *Journal of Virology*. 70(5), 3307-3312. https://jvi.asm.org/content/

Transcribed RNA." *Science*, 277(5325), 570-574. https://science.sciencemag.org/

[24] Wakita et al. (2005). "Production of infectious hepatitis C virus in tissue

3231.2008.01925.x.

*Discovery of Hepatitis C Virus: Nobel Prize in Physiology and Medicine 2020 DOI: http://dx.doi.org/10.5772/intechopen.96734*

[16] He et al. (1987). "Determining the Size of Non-A, Non-B Hepatitis Virus by Filtration." *Journal of Infectious Diseases*, 156(4), 636-640. https://pubmed.ncbi. nlm.nih.gov/3114389/.

[17] Houghton, Michael. (2019 ) "Hepatitis C Virus: 30 Years after Its Discovery." *Cold Spring Harb Perspect Med*, 9(12):a037069, 1-9. https:// pubmed.ncbi.nlm.nih.gov/31501269/

[18] Choo et al. (1989). "Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome." *Science*, 244(4902), 359-362. https:// pubmed.ncbi.nlm.nih.gov/2523562/.

[19] Alter, Harvey J., Houghton, Michael.,and Rice, Charles M. "Press release: The Nobel Prize in Physiology or Medicine 2020." *The Nobel Prize*. https://www.nobelprize.org/prizes/ medicine/2020/press-release/.

[20] Houghton, Michael. (2009). "Discovery of the hepatitis C virus." Liver International, 29(s1), 82-88. https://doi.org/10.1111/j.1478- 3231.2008.01925.x.

[21] Blight, Keril J., and Rice, Charles M. (1997). "Secondary Structure Determination of the Conserved 98-Base Sequence at the 39 Terminus of Hepatitis C Virus Genome RNA." Journal of Virology. 71(10), 7345-7352. https://jvi.asm.org/content/71/10/7345.

[22] Tanka et al. (1996). "Structure of the 39 Terminus of the Hepatitis C Virus Genome." *Journal of Virology*. 70(5), 3307-3312. https://jvi.asm.org/content/ 70/5/3307.

[23] Kolykhalov et al. (1997). "Transmission of Hepatitis C by Intrahepatic Inoculation with Transcribed RNA." *Science*, 277(5325), 570-574. https://science.sciencemag.org/ content/277/5325/570.

[24] Wakita et al. (2005). "Production of infectious hepatitis C virus in tissue

culture from a cloned viral genome." *Nature Medicine*, 11(7), 791-796. https:// doi.org/10.1038/nm1268.

[25] Ilboudo et al. (2014). "Overexpression of phosphatidylinositol 4-kinase type III?? is associated with undifferentiated status and poor prognosis of human hepatocellular carcinoma." *BMC Cancer*, 14(7), 1-8. https://doi.org/10.1186/1471-2407-14-7.

[26] Harak et al. (2016). "Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture." *Nature Microbiology*, 2, 1-13. https://doi.org/10.1038/ nmicrobiol.2016.247.

[27] Sarhan et al. (2017). "Glycogen synthase kinase 3?? inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism." *Scientific Reports*, 7(1), 1-12. https://doi.org/10.1038/s41598-017- 02648-6.

[28] Rosa et al. (2005). "Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders." *PANS*, 102(5), 18544-18549. https://doi.org/10.1073/ pnas.0509402102.

[29] Li, Hui-Chun., and Lo, Shih-Yen. (2015). "Hepatitis C virus: Virology, diagnosis and treatment." World Journal of Hepatology, 7(10), 1377. https:// www.ncbi.nlm.nih.gov/pmc/articles/ PMC4450201/.

**10**

*Advances in Hepatology*

**References**

[1] D'Souza, Raymond., & Foster, Graham R. (2004). "Diagnosis and treatment of hepatitis C." Journal of the Royal Society of Medicine, 97(5), 223-225. https://www.ncbi.nlm.nih.gov/ began and where we are now." Virology Journal, 10(1), 239. http://www. virologyj.com/content/10/1/23.

[9] Pilcher, Carl B. (2015). "Explorer, Nobel Laureate, Astrobiologist: Things

Blumberg." Astrobiology, 15(1), 1-14. https://doi.org/10.1089/ast.2013.1401.

[10] Palese, Peter. (2016). "Profile of

Bartenschlager, and Michael J. Sofia, 2016 Lasker-DeBakey Clinical Medical Research Awardees." *Proceedings of the National Academy of Sciences*, 113(49), 13934-13937. https://doi.org/10.1073/

[11] Alter et al. (1972). "Posttransfusion

Commercial and Hepatitis-B Antigen-Positive Donors". *Annals of Internal Medicine*, 77(5), 691-699. https:// pubmed.ncbi.nlm.nih.gov/4628213/.

[12] Alter et al. (1975a). "CLINICAL AND SEROLOGICAL ANALYSIS OF TRANSFUSION-ASSOCIATED HEPATITIS." *The Lancet*, 306(7940), 838-841. https://doi.org/10.1016/

[13] Alter et al. (1975b). "The emerging pattern of post-transfusion hepatitis." *The American Journal of the Medical Sciences*, 270(2), 329-334. https:// pubmed.ncbi.nlm.nih.gov/1235474/.

[14] Tabor et al. (1978). "TRANS-MISSION OF NON-A, NON-B HEPATITIS FROM MAN TO

S0140-6736(78)90132-0.

asm.org/content/41/2/816.

CHIMPANZEE." *The Lancet*, 311(8062), 463-466. https://doi.org/10.1016/

[15] Feinstone et al. (1983). "Inactivation of Hepatitis B Virus and Non-A, Non-B Hepatitis by Chloroform." *Infection and Immunity*, 41(2), 816-821. https://iai.

You Never Knew about Barry

Charles M. Rice, Ralf F. W.

Hepatitis After Exclusion of

S0140-6736(75)90234-2.

pnas.1616592113.

[2] Bukh, Jens. (2016). "The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control." Journal of Hepatology, 65(1), S2-S21. https://doi.org/10.1016/j.jhep.2016.07.035.

[3] Horsley-Silva, Jennifer L., and Vargas, Hugo E. "New Therapies for

*Gastroenterology & Hepatology*, 13(1), 22-31. https://pubmed.ncbi.nlm.nih.

[4] Nobel Prize. (2020, October 6). "Announcement of the 2020 Nobel Prize in Physiology or Medicine."[Video]. *You Tube*. https://youtu.be/BTu6uOWLKR4.

[5] Morozov, Vladimir Alexei., and Lagaye, Sylvie. (2018). "Hepatitis C virus: Morphogenesis, infection and therapy." World Journal of Hepatology, 10(2), 186-212. https://pubmed.ncbi.

[6] Ginsau, M A., and Ahmed, U A. (2019) "Examination of Blood for Hepatitis B Virus (HBV) and possible

nlm.nih.gov/29527256/.

Transmission by Mosquito (Aedesaegypti)." *IOSR Journal of Environmental Science, Toxicology and Food Technology (IOSR-JESTFT)*, 13(2),

DOI: 10.9790/2402-1302014851.

[7] Thomas et al. (2015). "Viral

ncbi.nlm.nih.gov/25646383/.

[8] Gerlich, Wolfram H. (2013).

Hepatitis: Past and Future of HBV and HDV." *Cold Spring Harbor Perspectives in Medicine*, 5(2), 1-11. https://pubmed.

"Medical Virology of Hepatitis B: how it

Hepatitis C Virus Infection."

gov/28420944/.

pmc/articles/PMC1079461/.

**13**

Section 2

Hepatitis C Virus

Characteristics and Evolution

### Section 2

## Hepatitis C Virus Characteristics and Evolution

**15**

**Chapter 2**

**Abstract**

**1. Introduction**

HCV-positive women [4].

Hepatitis C: An Overview

Hepatitis C virus (HCV) has infected approximatelly 130–170 milion individuals in the form of chronic liver infection and hepatocellular carcinoma. In the majority of patients with the increased risk for hepatocellular carcinoma the initial rearrangement is fibrosis. HCV is a bloodborne virus. The most common route of the infection are drug use, injections, unsafe health care performance, transfusion and sexual transmission. The incubation period ranges from 2 to 6 weeks in case of HCV. HCV infection is diagnosed in the process of detecting of anti-HCV antibodies and if positive, a nucleic acid test for HCV ribonucleic acid (RNA) is done. Currently, the most promising treatment agents are direct-acting antivirals (DAAs). They have shown limited viral resistance, long treatment duration and higher cost with no proven benefits in the prevention of graft reinfections in HCV individuals. In the light of the aforementioned, there is a need to a more dubious research in the

The word "hepatitis" is defined as the liver inflammation. In the majority of individuals it is due to genetic diseases, iatrogenic effect (certain medications), sexual intercourse, being born to a mother who has hepatitis C, transfusion, tattooing, illegal drug use or high alcohol intake. Prior to 1992, while the screening of the blood supplies started in the US, hepatitis C was most commonly spread through blood transfusions, organ transplants and haemodialysis treatment. Hepatitis C virus (HCV) has infected approximately 130–170 million individuals in the form of

In the majority of patients with an increased risk for hepatocellular carcinoma,

Recommended HCV routine testing is based on the high-risk individuals such as risk the use of illegal drugs, clotting factors prior 1987, received blood/organs before 1992, chronic haemodialysis, liver disease, healthcare, emergency, healthcare workers after needlestick injuries in case of to HCV-positive blood, children born to

The routine HCV testing is not recommended in the healthcare setting, especially in the emergency and public safety professionals, pregnant individuals,

the initial rearrangement is fibrosis. HCV is a bloodborne virus (**Figure 1**) [2]. Chronic hepatitis C (CHC) patients are at high risk to develop life-threatening complications, including cirrhosis in 20% of cases and hepatocellular carcinoma

*Syed Manzoor Kadri and Marija Petkovic*

quest for the effective therapeutic modalities.

**Keywords:** HCV, diagnosis, management, vaccine

chronic liver infection and hepatocellular carcinoma [1].

in-home contacts of HCV-positive individuals etc.

(HCC) at an incidence of 4–5% per year in cirrhotic patients [3].

## **Chapter 2** Hepatitis C: An Overview

*Syed Manzoor Kadri and Marija Petkovic*

#### **Abstract**

Hepatitis C virus (HCV) has infected approximatelly 130–170 milion individuals in the form of chronic liver infection and hepatocellular carcinoma. In the majority of patients with the increased risk for hepatocellular carcinoma the initial rearrangement is fibrosis. HCV is a bloodborne virus. The most common route of the infection are drug use, injections, unsafe health care performance, transfusion and sexual transmission. The incubation period ranges from 2 to 6 weeks in case of HCV. HCV infection is diagnosed in the process of detecting of anti-HCV antibodies and if positive, a nucleic acid test for HCV ribonucleic acid (RNA) is done. Currently, the most promising treatment agents are direct-acting antivirals (DAAs). They have shown limited viral resistance, long treatment duration and higher cost with no proven benefits in the prevention of graft reinfections in HCV individuals. In the light of the aforementioned, there is a need to a more dubious research in the quest for the effective therapeutic modalities.

**Keywords:** HCV, diagnosis, management, vaccine

#### **1. Introduction**

The word "hepatitis" is defined as the liver inflammation. In the majority of individuals it is due to genetic diseases, iatrogenic effect (certain medications), sexual intercourse, being born to a mother who has hepatitis C, transfusion, tattooing, illegal drug use or high alcohol intake. Prior to 1992, while the screening of the blood supplies started in the US, hepatitis C was most commonly spread through blood transfusions, organ transplants and haemodialysis treatment. Hepatitis C virus (HCV) has infected approximately 130–170 million individuals in the form of chronic liver infection and hepatocellular carcinoma [1].

In the majority of patients with an increased risk for hepatocellular carcinoma, the initial rearrangement is fibrosis. HCV is a bloodborne virus (**Figure 1**) [2].

Chronic hepatitis C (CHC) patients are at high risk to develop life-threatening complications, including cirrhosis in 20% of cases and hepatocellular carcinoma (HCC) at an incidence of 4–5% per year in cirrhotic patients [3].

Recommended HCV routine testing is based on the high-risk individuals such as risk the use of illegal drugs, clotting factors prior 1987, received blood/organs before 1992, chronic haemodialysis, liver disease, healthcare, emergency, healthcare workers after needlestick injuries in case of to HCV-positive blood, children born to HCV-positive women [4].

The routine HCV testing is not recommended in the healthcare setting, especially in the emergency and public safety professionals, pregnant individuals, in-home contacts of HCV-positive individuals etc.

**Figure 1.**

*Fibrogenesis. World J Gastroenterol. 2014. Doi: 10.3748/wjg.v20.i32.11033.*

### **2. Epidemiology of hepatitis C virus**

Hepatitis C is a disease with a worldwide burden, with the variable prevalence among major geographic areas. WHO estimates that about 170 million people or 3% of the world's population are infected with HCV [5].

The regions with high incidence are Eastern Mediterranean and European, with a prevalence of 2.3% and 1.5% respectively (**Figure 2**).

The estimated global prevalence of HCV infection is 3% which translates to over 180 million people worldwide [6].

High seroprevalence is noted in Asian and African countries. Egypt reported a seroprevalence of about 22% [7] and is highest in the world. A substantial regional difference exists in the distribution of HCV genotypes in the world. In Mexico, the estimated prevalence of HCV (2001–2002) was 1.2%. In the UK region, it has been estimated that nearly 200,000 adult individuals are HCV carriers. In Australia, the prevalence is estimated to be 2.3%. In Pakistan, HCV prevalence studies detected


**17**

**Figure 3.**

*Hepatitis C virus- an overview. 2018. Sagar Aryal*

*Hepatitis C: An Overview*

Saudi Arabia and Yemen.

**3. HCV characteristics**

genotypes and over 80 subtypes [8].

NS3, NS4A, NS4B, NS5A, NS5B).

**3.2 Genetic variations of HCV**

during assembly or infection (**Figure 4**).

**3.1 HCV genotype**

*DOI: http://dx.doi.org/10.5772/intechopen.94879*

that 751 out of 16,400 (4.57%) patients are +HCV Ab, while the rated are lower in

Hepatitis C virus is an RNA viral microorganism. This virus belongs to the Flaviviridae family, genus Hepacivirus. It has one serotype, but minimum 6 major

single-stranded RNA genome composed of a long open reading frame (ORF)

flanked by untranslated regions (UTR's) at both the ends (**Figure 3**).

NS4A-NS4B, NS4B-NS4B, NS4B-NS5A and NS5A-NS5B junctions [9].

The HCV virion is 55–65 nm in diameter. It consists of a 9.6 kbp positive-sense

The genome of HCV is thought to encode at least 10 proteins, of which 3 are structural (core, envelope glycoproteins E1, E2) and 6 nonstructural proteins (NS2,

HCV also expresses p7, a membrane-associated ion channel that may function

The HCV RNA sequences are highly heterogeneous. HCV is classified into 11 genotypes [1–11]. The several genotypes form further subtypes such as a, b, c etc.

Two viral proteases are involved in the processing of HCV nonstructural proteins: NS2, a zinc-dependent metalloproteinase that cleaves between proteins NS2 and NS3, and NS3/4A, a serine protease that cleaves between the NS3-NS4A,

0.49% (1995–2000.), with higher rates in Thailand (3.2–5.6%).

In Asia, the HCV prevalence among blood donors has been estimated lower than

**Figure 2.** *HCV prevalence.* that 751 out of 16,400 (4.57%) patients are +HCV Ab, while the rated are lower in Saudi Arabia and Yemen.

In Asia, the HCV prevalence among blood donors has been estimated lower than 0.49% (1995–2000.), with higher rates in Thailand (3.2–5.6%).

### **3. HCV characteristics**

#### **3.1 HCV genotype**

*Advances in Hepatology*

**2. Epidemiology of hepatitis C virus**

**Figure 1.**

180 million people worldwide [6].

of the world's population are infected with HCV [5].

a prevalence of 2.3% and 1.5% respectively (**Figure 2**).

*Fibrogenesis. World J Gastroenterol. 2014. Doi: 10.3748/wjg.v20.i32.11033.*

Hepatitis C is a disease with a worldwide burden, with the variable prevalence among major geographic areas. WHO estimates that about 170 million people or 3%

The regions with high incidence are Eastern Mediterranean and European, with

The estimated global prevalence of HCV infection is 3% which translates to over

High seroprevalence is noted in Asian and African countries. Egypt reported a seroprevalence of about 22% [7] and is highest in the world. A substantial regional difference exists in the distribution of HCV genotypes in the world. In Mexico, the estimated prevalence of HCV (2001–2002) was 1.2%. In the UK region, it has been estimated that nearly 200,000 adult individuals are HCV carriers. In Australia, the prevalence is estimated to be 2.3%. In Pakistan, HCV prevalence studies detected

**16**

**Figure 2.** *HCV prevalence.*

Hepatitis C virus is an RNA viral microorganism. This virus belongs to the Flaviviridae family, genus Hepacivirus. It has one serotype, but minimum 6 major genotypes and over 80 subtypes [8].

The HCV virion is 55–65 nm in diameter. It consists of a 9.6 kbp positive-sense single-stranded RNA genome composed of a long open reading frame (ORF) flanked by untranslated regions (UTR's) at both the ends (**Figure 3**).

The genome of HCV is thought to encode at least 10 proteins, of which 3 are structural (core, envelope glycoproteins E1, E2) and 6 nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B).

HCV also expresses p7, a membrane-associated ion channel that may function during assembly or infection (**Figure 4**).

Two viral proteases are involved in the processing of HCV nonstructural proteins: NS2, a zinc-dependent metalloproteinase that cleaves between proteins NS2 and NS3, and NS3/4A, a serine protease that cleaves between the NS3-NS4A, NS4A-NS4B, NS4B-NS4B, NS4B-NS5A and NS5A-NS5B junctions [9].

#### **3.2 Genetic variations of HCV**

The HCV RNA sequences are highly heterogeneous. HCV is classified into 11 genotypes [1–11]. The several genotypes form further subtypes such as a, b, c etc.

**Figure 3.** *Hepatitis C virus- an overview. 2018. Sagar Aryal*

The classification is made according to the nucleotide sequence, variable infectivity and pathogenicity determining the progression rate of cirrhosis and hepatocellular carcinoma [11].

At this point, genotype 1 is the most prevalent (46%), then genotype 3,2 and 4 [12].

Core, a 191-amino acid polypeptide, may be involved in hepatocarcinogenesis and steatosis [13].

The importance of HCV genotype is highlighted in the case of the treatment response and the therapy duration.

The HCV genotype is characterised by the detection of antibodies against HCV genotype-specific epitopes with the application of competitive EIA.

HCV subtyping is of paramount importance in case of epidemics/pandemics, especially in case of epidemiological studies.

#### **4. Pathogenesis of hepatitis C virus**

The most common route of the infection is drug abuse, injections, unsafe health care performance, transfusion and sexual transmission.

The incubation period ranges from 2 to 6 weeks in case of HCV. HCV infection is diagnosed in the process of detecting anti-HCV antibodies and if possible, a nucleic acid test for HCV ribonucleic acid (RNA) is done [14].

The pathogenesis is characterised by HCV infected hepatocytes that may be destructed by HCV-specific CTL clones. The apoptotic mechanism is Fas ligand, TNF-α or perforin-based mechanism [15].

In the majority of cases, there is a slowly progressive asymptomatic hepatitis, with persistent viremia. The chronic form of the disease has a higher rate of progression to cirrhosis over a period of 20 years.

The exacerbation of the disease is characterised by elevated alanine aminotransferase activity. HCV –specific antibodies are detectable 7 to 31 weeks after the initial infection. Thus, the humoral immunity is highly variable and aimed towards the HCV core, envelope, NS3 and NS4 proteins [16].

The characteristic parenchyma impairments are the triad of steatosis, bile duct damage and the portal tracts [17].

**19**

*Hepatitis C: An Overview*

aminotransferase activity.

noma (HCC) [18].

T-cell response.

**5.1 Acute hepatitis**

pain and jaundice [20].

**5.2 Chronic hepatitis**

**5.3 Hepatocellular carcinoma**

**6. Diagnostic assessment**

significant [23].

28B [19].

*DOI: http://dx.doi.org/10.5772/intechopen.94879*

Hepatic steatosis presents with large droplets of fat vacuoles in the cytoplasm

of hepatocytes. In 20% of chronic hepatitis C cases, there is an eosinophilic deposit in the cytoplasm of periportal hepatocytes. Furthermore, the level of necroinflammation, fibrosis and cirrhosis depends on the serum alanine

consumption increase the risk of hepatic disease progression.

**5. Clinical manifestations of hepatitis C virus**

Predisposing factors such as viral co-infection (HBV etc.) and high alcohol

Chronic active hepatitis frequently leads to the onset of hepatocellular carci-

It has been postulated that in the case of HCV infection, the HCV-immune specific reaction is not adequate to control the viral replication due to high level of

The variety of polymorphism is associated with HCV prognostic diversity. The major cytokine involved in the molecular HCV infection pathway is the interleukin

The incubation period for HCV is 7 weeks (2–26 weeks) after the initial exposure. The acute HCV infection presents with fever, fatigue, decreased appetite, nausea, vomiting, abdominal cramps, dark coloured faeces, grey facial skin, joint

In the patient with chronic hepatitis, the hepatic function is impaired. Additional symptoms are anorexia, nausea, right upper quadrant pain, dark coloured urine and

The oncogenesis in the patients with chronic virus inflammation leads to the

In the majority of individuals, HCV viremia may be present in spite of normal serum ALT levels. Thus, the virological confirmation of HCV infection is more

There is an HCV testing protocol such as to test the asymptomatic individuals: EIA for anti-HCV if negative (non-reactive) test no further if positive repeat testing or RIBA for anti-HCV. Recombinant immunoblot assays (RIBA) can be used to

The other possible testing pathway is to perform RT-PCR for HCV RNA if nega-

In case RIBA test for anti-HCV is negative, [25] do not perform the further evaluation. In case the test is indeterminate (PCR negative, ALT normal or positive PCR, abnormal ALP continue with medial evaluation. In case both tests are posi-

pruritus. The serum level of ALT is either normal or elevated [21].

tive or if the positive result, proceed with medical evaluation [24].

onset of necrosis, regeneration and cirrhosis [22].

confirm the presence of anti-HCV antibodies.

tive, continue with the medical evaluation.

*Hepatitis C: An Overview DOI: http://dx.doi.org/10.5772/intechopen.94879*

*Advances in Hepatology*

carcinoma [11].

**Figure 4.** *HCV genome.*

and steatosis [13].

response and the therapy duration.

especially in case of epidemiological studies.

care performance, transfusion and sexual transmission.

acid test for HCV ribonucleic acid (RNA) is done [14].

**4. Pathogenesis of hepatitis C virus**

TNF-α or perforin-based mechanism [15].

gression to cirrhosis over a period of 20 years.

HCV core, envelope, NS3 and NS4 proteins [16].

damage and the portal tracts [17].

The classification is made according to the nucleotide sequence, variable infectivity and pathogenicity determining the progression rate of cirrhosis and hepatocellular

At this point, genotype 1 is the most prevalent (46%), then genotype 3,2 and 4 [12]. Core, a 191-amino acid polypeptide, may be involved in hepatocarcinogenesis

The importance of HCV genotype is highlighted in the case of the treatment

genotype-specific epitopes with the application of competitive EIA.

The HCV genotype is characterised by the detection of antibodies against HCV

HCV subtyping is of paramount importance in case of epidemics/pandemics,

The most common route of the infection is drug abuse, injections, unsafe health

The incubation period ranges from 2 to 6 weeks in case of HCV. HCV infection is diagnosed in the process of detecting anti-HCV antibodies and if possible, a nucleic

The pathogenesis is characterised by HCV infected hepatocytes that may be destructed by HCV-specific CTL clones. The apoptotic mechanism is Fas ligand,

In the majority of cases, there is a slowly progressive asymptomatic hepatitis, with persistent viremia. The chronic form of the disease has a higher rate of pro-

The exacerbation of the disease is characterised by elevated alanine aminotransferase activity. HCV –specific antibodies are detectable 7 to 31 weeks after the initial infection. Thus, the humoral immunity is highly variable and aimed towards the

The characteristic parenchyma impairments are the triad of steatosis, bile duct

**18**

Hepatic steatosis presents with large droplets of fat vacuoles in the cytoplasm of hepatocytes. In 20% of chronic hepatitis C cases, there is an eosinophilic deposit in the cytoplasm of periportal hepatocytes. Furthermore, the level of necroinflammation, fibrosis and cirrhosis depends on the serum alanine aminotransferase activity.

Predisposing factors such as viral co-infection (HBV etc.) and high alcohol consumption increase the risk of hepatic disease progression.

Chronic active hepatitis frequently leads to the onset of hepatocellular carcinoma (HCC) [18].

It has been postulated that in the case of HCV infection, the HCV-immune specific reaction is not adequate to control the viral replication due to high level of T-cell response.

The variety of polymorphism is associated with HCV prognostic diversity. The major cytokine involved in the molecular HCV infection pathway is the interleukin 28B [19].

#### **5. Clinical manifestations of hepatitis C virus**

#### **5.1 Acute hepatitis**

The incubation period for HCV is 7 weeks (2–26 weeks) after the initial exposure. The acute HCV infection presents with fever, fatigue, decreased appetite, nausea, vomiting, abdominal cramps, dark coloured faeces, grey facial skin, joint pain and jaundice [20].

#### **5.2 Chronic hepatitis**

In the patient with chronic hepatitis, the hepatic function is impaired. Additional symptoms are anorexia, nausea, right upper quadrant pain, dark coloured urine and pruritus. The serum level of ALT is either normal or elevated [21].

#### **5.3 Hepatocellular carcinoma**

The oncogenesis in the patients with chronic virus inflammation leads to the onset of necrosis, regeneration and cirrhosis [22].

#### **6. Diagnostic assessment**

In the majority of individuals, HCV viremia may be present in spite of normal serum ALT levels. Thus, the virological confirmation of HCV infection is more significant [23].

There is an HCV testing protocol such as to test the asymptomatic individuals: EIA for anti-HCV if negative (non-reactive) test no further if positive repeat testing or RIBA for anti-HCV. Recombinant immunoblot assays (RIBA) can be used to confirm the presence of anti-HCV antibodies.

The other possible testing pathway is to perform RT-PCR for HCV RNA if negative or if the positive result, proceed with medical evaluation [24].

In case RIBA test for anti-HCV is negative, [25] do not perform the further evaluation. In case the test is indeterminate (PCR negative, ALT normal or positive PCR, abnormal ALP continue with medial evaluation. In case both tests are positive, continue with the medical evaluation.

A serologic screening test is recommended to perform on individuals in the high-risk groups and nucleic acid tests are recommended to confirm the active HCV infections.

#### **6.1 Laboratory diagnosis of HCV**

Nowadays, HCV infection is detected by the use of serologic tests to detect HCV antibodies. Enzyme immunoassay (EIA) shows false negative in patients on haemodialysis. Immunodeficiency, and false-positive in an autoimmune disorder.

Recombinant immunoblot assay (RIBA) is a molecular assay that targets the amplification technique to detect HCV RNA.

A positive polymerase chain reaction (PCR) confirms HCV infection.

At present, the second-generation enzyme immunoassay (EIA-2) for antibodies to HCV (anti-HCV) is the most recommended diagnostic modality. If positive, the diagnosis may be confirmed by RIBA to detect antibodies to individual HCV antigens.

Anti-HCV is detected by the enzyme-linked immunosorbent assay (ELISA). In EIA, conserved antigens from the HCV core, NS3,NS4 and NS5 are used in the diagnostic laboratory.

EIAs to detect anti-HCV antibody are recommended for screening the HCV infections. It is not recommended in infants younger than 18 months due to the possible reactivity with the maternal antibody [26].

The serological window period is 40 days.

A screening test is the rapid, point-of-care test (POCTs) developed to detect anti-HCV antibodies with high sensitivity and specificity (OraQuick, OraSure Technologies). This test detects anti-HCV antibodies in different specimens (fingerstick, venipuncture whole blood, serum, plasma, oral fluid [27].

Confirmatory test such as recombinant immunoblot assay (RIBA) is used to confirm the presence of antibodies against each of the several HCV proteins is assessed as individual bands on a membrane strip [28].

HCV RNA level in the serum is probably the first detectable marker of acute HCV infection – a few weeks prior to the appearance of anti-HCV antibody by several weeks [29].

In the period prior and after the treatment, detection of HCV RNA is used to monitor the disease status. The level of HCV RNA is not in correlation with the hepatic disease stadium.

#### **6.2 Molecular diagnosis of HCV**

Qualitative reverse transcription-polymerase chain reaction (RT-PCR) assays for HCV RNA are simpler than quantitative tests and adequate for confirmation of the diagnosis of HCV [30].

Serum alanine aminotransferase level (ALT) is inexpensive, routine and noninvasive. It is great value for monitoring the disease activity.

#### **6.3 Detection of viral RNA**

Detection of HCV RNA by PCR and nucleic acid amplification tests (NAT) is performed, such as Transcript-Mediated Amplification (TMA).

Qualitative HCV RNA detection is defined as the use of conventional RT-PCR or transcription-mediated amplification (TMA) [31].

Quantitative NAT test is available in the form of quantitative RT-PCR (qRT-PCR) and branched deoxyribonucleic acid (bDNA) technology.

**21**

*Hepatitis C: An Overview*

NS5A region.

**6.5 Liver biopsy**

modalities [33].

**7. Treatment**

treatment [38].

stage liver disease [39].

HCV infected individuals [32].

FIB4) are recommended.

peginterferon and ribavirin [35].

higher in genotypes 2 and 3 [37].

activity or therapeutic intervention [34].

*DOI: http://dx.doi.org/10.5772/intechopen.94879*

tion of viral antigens and viral nucleic acids.

**6.4 Detection of HCV core antigen**

The indirect tests detect antibody induced by virus replication, IgM for recent infection, IgG for recent or past infection. The direct tests are virus isolation, detec-

NATs test has higher specificity and sensitivity, but it is more time-consuming and in need of more sophisticated techniques. Currently, there are several generations of ELISA developed such as the one that uses the recombinant c100–3 epitope from the NS4 region, c22–3 and c33c from the HCV core and NS3 regions. The 4th generation of the anti-HCV assay is designed from the core, NS3, NS4A, NS4B and

The liver biopsy provides use of full information about the degree of fibrosis in

The main benefit is to further manage the treatment protocol. The liver biopsy can assess the degree of inflammation, fibrosis, co-morbidities and therapeutic

Activity (necro-inflammation) severity and progress. May fluctuate with disease

Fibrosis implies possible progression to cirrhosis or in advanced disease defined as 'bridging fibrosis.'. To assess the degree of fibrosis, non-invasive tests (APRI or

The initial HCV treatment was based on the application of interferon alfa,

feron against hepatitis by as yet undefined mechanisms [36].

The antiviral activity of interferon and peginterferon is based upon their ability to stimulate interferon-stimulated genes (ISGs) that have endogenous antiviral activities. Ribavirin is a nucleoside analogue that potentiates the effects of inter-

Until 2020, the standard chronic HCV therapy was the combination of peginterferon and ribavirin given for 24 or 48 weeks. This combination led to sustained clearance of HCV and remission disease in 40–50% of patients. The response rate is

Other oral regimens become available in 2015, 2016 and 2017. They represented a combination of several HCV RNA polymerase regimens – nucleoside and non-

In individuals with cirrhosis, there is a higher risk of developing HCC and end-

The combination of pegylated interferon plus ribavirin (PR) was the gold treatment standard (2000.). anti-HCV therapy requires weekly injections and is associated with numerous systemic side effects (flu-like symptoms, fatigue, etc.) [40]. The first approved in the USA according to FDA – boceprevir (Victrelis) and telaprevir (Incivek) for the treatment of chronic HCV genotype I infection [41].

In 2010, several HCV-specific protease inhibitors were approved for use: boceprevir, telaprevir and simeprevir specific to genotype 1 HCV. In 2013, sofosbuvir (HCV specific RNA polymerase inhibitor) was approved for the clinical

nucleoside, HCV NS5A antagonists and the HCV protease inhibitors.

The indirect tests detect antibody induced by virus replication, IgM for recent infection, IgG for recent or past infection. The direct tests are virus isolation, detection of viral antigens and viral nucleic acids.

#### **6.4 Detection of HCV core antigen**

NATs test has higher specificity and sensitivity, but it is more time-consuming and in need of more sophisticated techniques. Currently, there are several generations of ELISA developed such as the one that uses the recombinant c100–3 epitope from the NS4 region, c22–3 and c33c from the HCV core and NS3 regions. The 4th generation of the anti-HCV assay is designed from the core, NS3, NS4A, NS4B and NS5A region.

#### **6.5 Liver biopsy**

*Advances in Hepatology*

**6.1 Laboratory diagnosis of HCV**

amplification technique to detect HCV RNA.

possible reactivity with the maternal antibody [26]. The serological window period is 40 days.

as individual bands on a membrane strip [28].

vasive. It is great value for monitoring the disease activity.

transcription-mediated amplification (TMA) [31].

and branched deoxyribonucleic acid (bDNA) technology.

performed, such as Transcript-Mediated Amplification (TMA).

infections.

antigens.

diagnostic laboratory.

several weeks [29].

hepatic disease stadium.

diagnosis of HCV [30].

**6.3 Detection of viral RNA**

**6.2 Molecular diagnosis of HCV**

A serologic screening test is recommended to perform on individuals in the high-risk groups and nucleic acid tests are recommended to confirm the active HCV

Nowadays, HCV infection is detected by the use of serologic tests to detect HCV antibodies. Enzyme immunoassay (EIA) shows false negative in patients on haemo-

Recombinant immunoblot assay (RIBA) is a molecular assay that targets the

At present, the second-generation enzyme immunoassay (EIA-2) for antibodies to HCV (anti-HCV) is the most recommended diagnostic modality. If positive, the diagnosis may be confirmed by RIBA to detect antibodies to individual HCV

Anti-HCV is detected by the enzyme-linked immunosorbent assay (ELISA). In EIA, conserved antigens from the HCV core, NS3,NS4 and NS5 are used in the

EIAs to detect anti-HCV antibody are recommended for screening the HCV infections. It is not recommended in infants younger than 18 months due to the

A screening test is the rapid, point-of-care test (POCTs) developed to detect anti-HCV antibodies with high sensitivity and specificity (OraQuick, OraSure Technologies). This test detects anti-HCV antibodies in different specimens (fin-

Confirmatory test such as recombinant immunoblot assay (RIBA) is used to confirm the presence of antibodies against each of the several HCV proteins is assessed

HCV RNA level in the serum is probably the first detectable marker of acute HCV infection – a few weeks prior to the appearance of anti-HCV antibody by

In the period prior and after the treatment, detection of HCV RNA is used to monitor the disease status. The level of HCV RNA is not in correlation with the

Qualitative reverse transcription-polymerase chain reaction (RT-PCR) assays for HCV RNA are simpler than quantitative tests and adequate for confirmation of the

Serum alanine aminotransferase level (ALT) is inexpensive, routine and nonin-

Detection of HCV RNA by PCR and nucleic acid amplification tests (NAT) is

Qualitative HCV RNA detection is defined as the use of conventional RT-PCR or

Quantitative NAT test is available in the form of quantitative RT-PCR (qRT-PCR)

gerstick, venipuncture whole blood, serum, plasma, oral fluid [27].

dialysis. Immunodeficiency, and false-positive in an autoimmune disorder.

A positive polymerase chain reaction (PCR) confirms HCV infection.

**20**

The liver biopsy provides use of full information about the degree of fibrosis in HCV infected individuals [32].

The main benefit is to further manage the treatment protocol. The liver biopsy can assess the degree of inflammation, fibrosis, co-morbidities and therapeutic modalities [33].

Activity (necro-inflammation) severity and progress. May fluctuate with disease activity or therapeutic intervention [34].

Fibrosis implies possible progression to cirrhosis or in advanced disease defined as 'bridging fibrosis.'. To assess the degree of fibrosis, non-invasive tests (APRI or FIB4) are recommended.

#### **7. Treatment**

The initial HCV treatment was based on the application of interferon alfa, peginterferon and ribavirin [35].

The antiviral activity of interferon and peginterferon is based upon their ability to stimulate interferon-stimulated genes (ISGs) that have endogenous antiviral activities. Ribavirin is a nucleoside analogue that potentiates the effects of interferon against hepatitis by as yet undefined mechanisms [36].

Until 2020, the standard chronic HCV therapy was the combination of peginterferon and ribavirin given for 24 or 48 weeks. This combination led to sustained clearance of HCV and remission disease in 40–50% of patients. The response rate is higher in genotypes 2 and 3 [37].

In 2010, several HCV-specific protease inhibitors were approved for use: boceprevir, telaprevir and simeprevir specific to genotype 1 HCV. In 2013, sofosbuvir (HCV specific RNA polymerase inhibitor) was approved for the clinical treatment [38].

Other oral regimens become available in 2015, 2016 and 2017. They represented a combination of several HCV RNA polymerase regimens – nucleoside and nonnucleoside, HCV NS5A antagonists and the HCV protease inhibitors.

In individuals with cirrhosis, there is a higher risk of developing HCC and endstage liver disease [39].

The combination of pegylated interferon plus ribavirin (PR) was the gold treatment standard (2000.). anti-HCV therapy requires weekly injections and is associated with numerous systemic side effects (flu-like symptoms, fatigue, etc.) [40].

The first approved in the USA according to FDA – boceprevir (Victrelis) and telaprevir (Incivek) for the treatment of chronic HCV genotype I infection [41].

#### *Advances in Hepatology*

Both drugs are classified as NS3/4A protease inhibitors, 24-28wk duration therapy, administered in combination with PR. FDA approved the different NS3/4A protease inhibitor named simeprevir (2013).

The HCV NS5B protein is an essential enzyme (RNA-dependant RNA polymerase) in HCV viral replication and has been a prime target in the search for antiviral therapies [42].

Adverse effects with interferon treatment: anaemia, neutropenia, rash, skin reactions, anorectal signs, elevated uric acid, bilirubin levels etc [43].

In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. In 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni were approved by the FDA.

The highly significant antiviral treatment regimens are PEG-IFN + Ribavirin, − Telaprevir or boceprevir in genotype 1, -Sofosbuvir + Ribavirin ± PEG-IFN in genotypes 1,2,3 and 4, Simeprevir +PEG-IFN + Ribavirin in genotype 1 [44].

HCV has several genotypes detected. Therefore, an effective vaccine must be multivalent to have a beneficial treatment outcome.

There is no vaccine for Hepatitis C. The only way to prevent Hepatitis C is by avoiding behaviour that can spread the disease, especially injection drug use.

#### **8. Prevention and control of hepatitis C**

Screening of blood donors and screening for the presence of HCV prior to any transfusion of blood.

The use of sterile needles in case of medical and dental procedures, tattooing, or other percutaneous exposures [45].

Alcohol-intake decreased consumption or reduction will improve the overall health of an individual.

#### **9. Conclusion**

Currently, the most promising treatment agents are direct-acting antiviral (DAAs). They have shown limited viral resistance, long treatment duration and higher cost with no proven benefits in the prevention of graft reinfections in HCV individuals.

In light of the aforementioned, there is a need for more dubious research in the quest for the effective therapeutic modalities.

In summary, the diagnostic algorithm of Hepatitis C depends on the clinical context. In asymptomatic, low-risk subjects, who are found to be anti-HCV positive by EIA-2, the diagnosis of HCV infection needs to be confirmed, especially if the initial biochemical tests reveal normal ALT levels.

**23**

**Author details**

Syed Manzoor Kadri1

\* and Marija Petkovic2

1 Disease Control, Directorate of Health Services, Kashmir, India

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 University of Medicine, Belgrade, Serbia

provided the original work is properly cited.

\*Address all correspondence to: kadrism@gmail.com

*Hepatitis C: An Overview*

*DOI: http://dx.doi.org/10.5772/intechopen.94879*

*Hepatitis C: An Overview DOI: http://dx.doi.org/10.5772/intechopen.94879*

*Advances in Hepatology*

antiviral therapies [42].

were approved by the FDA.

transfusion of blood.

health of an individual.

**9. Conclusion**

individuals.

protease inhibitor named simeprevir (2013).

Both drugs are classified as NS3/4A protease inhibitors, 24-28wk duration therapy, administered in combination with PR. FDA approved the different NS3/4A

The HCV NS5B protein is an essential enzyme (RNA-dependant RNA polymerase) in HCV viral replication and has been a prime target in the search for

Adverse effects with interferon treatment: anaemia, neutropenia, rash, skin

The highly significant antiviral treatment regimens are PEG-IFN + Ribavirin, − Telaprevir or boceprevir in genotype 1, -Sofosbuvir + Ribavirin ± PEG-IFN in geno-

HCV has several genotypes detected. Therefore, an effective vaccine must be

There is no vaccine for Hepatitis C. The only way to prevent Hepatitis C is by avoiding behaviour that can spread the disease, especially injection drug use.

Screening of blood donors and screening for the presence of HCV prior to any

The use of sterile needles in case of medical and dental procedures, tattooing, or

Alcohol-intake decreased consumption or reduction will improve the overall

Currently, the most promising treatment agents are direct-acting antiviral (DAAs). They have shown limited viral resistance, long treatment duration and higher cost with no proven benefits in the prevention of graft reinfections in HCV

In light of the aforementioned, there is a need for more dubious research in the

In summary, the diagnostic algorithm of Hepatitis C depends on the clinical context. In asymptomatic, low-risk subjects, who are found to be anti-HCV positive by EIA-2, the diagnosis of HCV infection needs to be confirmed, especially if the

In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. In 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni

reactions, anorectal signs, elevated uric acid, bilirubin levels etc [43].

types 1,2,3 and 4, Simeprevir +PEG-IFN + Ribavirin in genotype 1 [44].

multivalent to have a beneficial treatment outcome.

**8. Prevention and control of hepatitis C**

quest for the effective therapeutic modalities.

initial biochemical tests reveal normal ALT levels.

other percutaneous exposures [45].

**22**

### **Author details**

Syed Manzoor Kadri1 \* and Marija Petkovic2

1 Disease Control, Directorate of Health Services, Kashmir, India

2 University of Medicine, Belgrade, Serbia

\*Address all correspondence to: kadrism@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[24] Verónica Saludes, Victoria

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v20.i11.2785

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Terminology and Definition. Liver Pathology for Clinicians pp 23-44| Cite as

[18] Philippe J. Zamor, Andrew S.

#### *Hepatitis C: An Overview DOI: http://dx.doi.org/10.5772/intechopen.94879*

Terminology and Definition. Liver Pathology for Clinicians pp 23-44| Cite as

[18] Philippe J. Zamor, Andrew S. deLemos, Mark W. Russo. Viral hepatitis and hepatocellular carcinoma: etiology and management. J Gastrointest Oncol. 2017 Apr; 8(2): 229-242.

[19] *Rau M, Baur K, Geier A*Host genetic variants in the pathogenesis of hepatitis C.*Viruses. 2012 Dec; 4(12):3281-302.*

[20] Sheetal Trivedi, Satyapramod Murthy, Himanshu Sharma, Alex S. Hartlage, Arvind Kumar, Sashi Gadi, Peter Simmonds, Lokendra V. Chauhan, Troels K. H. Scheel, Eva Billerbeck, Peter D. Burbelo, Charles M. Rice, W. Ian Lipkin, Kurt Vandergrift, John M. Cullen, Amit Kapoor Viral persistence, liver disease and host response in **Hepatitis C**-like virus rat model. Hepatology. Author manuscript; available in PMC 2019 Aug 1.

[21] Shiu-Wan Chan. Establishment of chronic **hepatitis C** virus infection: Translational evasion of oxidative defence. World J Gastroenterol. 2014 Mar 21; 20(11): 2785-2800. Published online 2014 Mar 21. doi: 10.3748/wjg. v20.i11.2785

[22] Giuseppe Castello, Susan Costantini, Stefania Scala. Targeting the inflammation in **HCV**-associated hepatocellular **carcinoma**: a role in the prevention and treatment. J Transl Med. 2010; 8: 109. Published online 2010 Nov 3.

[23] *Chevaliez S, Pawlotsky JM.* How to use virological tools for optimal management of chronic hepatitis C.*. Liver Int. 2009 Jan; 29 Suppl 1():9-14.*

[24] Verónica Saludes, Victoria González, Ramon Planas, Lurdes Matas, Vicente Ausina, and Elisa Martró. Tools for the diagnosis of hepatitis C virus infection and hepatic fibrosis staging. World J Gastroenterol. 2014 Apr 7; 20(13): 3431-3442.

[25] Maria Alice Sant'ana Zarife, Eliana Almeida Gomes Reis, Mitermayer G. Reis. Indeterminate RIBA results were associated with the absence of hepatitis C virus RNA (HCV-RNA) in blood donors. Rev. Soc. Bras. Med. Trop. vol.47 no.1 Uberaba Jan./Feb. 2014

[26] *Campos-Outcalt D.* Hepatitis C: new CDC screening recommendations.*J Fam Pract. 2012 Dec; 61(12):744-6.*

[27] *Scalioni Lde P, Cruz HM, de Paula VS, Miguel JC, Marques VA, Villela-Nogueira CA, Milagres FA, Cruz MS, Bastos FI, Andrade TM, Motta-Castro AR, Lewis-Ximenez LL, Lampe E, Villar LM.* Performance of rapid hepatitis C virus antibody assays among high- and low-risk populations.*. J Clin Virol. 2014 Jul; 60(3):200-5.*

[28] *Martin P, Fabrizi F, Dixit V, Quan S, Brezina M, Kaufman E, Sra K, DiNello R, Polito A, Gitnick G* Automated RIBA hepatitis C virus (HCV) strip immunoblot assay for reproducible HCV diagnosis.. *J Clin Microbiol. 1998 Feb; 36(2):387-90.*

[29] *Chevaliez S, Pawlotsky JM.*How to use virological tools for optimal management of chronic hepatitis C.*. Liver Int. 2009 Jan; 29 Suppl 1():9-14.*

[30] Philippe Halfon, Marc Bourlière, Guillaume Pénaranda, Hacène Khiri, Denis Ouzan. Real-Time PCR Assays for Hepatitis C Virus (HCV) RNA Quantitation Are Adequate for Clinical Management of Patients with Chronic HCV Infection. J Clin Microbiol. 2006 Jul; 44(7): 2507-2511.

[31] Mel Krajden, Rainer Ziermann, Asphani Khan, Annie Mak, Kimmy Leung, David Hendricks,2 and Lorraine Comanor. Qualitative Detection of Hepatitis C Virus RNA: Comparison of Analytical Sensitivity, Clinical Performance, and Workflow of the Cobas Amplicor HCV Test Version 2.0 and the HCV RNA

**24**

*Advances in Hepatology*

Gastroenterol

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PhD, MPH..

Sep-Oct;106(5):361-5.

[1] Takafumi Saito, Yoshiyuki Ueno. Transmission of hepatitis C virus: selflimiting hepatitis or chronic hepatitis? 2013 Nov 7;19(41):6957-61. World J

and *Pegivirus* within the *Flaviviridae* family. J Gen Virol. 2016 Nov; 97(11):

[10] Donald B. Smith, Paul Becher, Jens Bukh, Ernest A. Gould, Gregor Meyers, Thomas Monath, A. Scott Muerhoff, Alexander Pletnev, Rebecca Rico-Hesse,

[12] *Chevaliez S, Pawlotsky JM.* Hepatitis

*Lo SY.* Production and pathogenicity of hepatitis C virus core gene products.*. World J Gastroenterol. 2014 Jun 21;* 

C virus: virology, diagnosis and management of antiviral therapy.*. World J Gastroenterol. 2007 May 7;* 

[13] *Li HC, Ma HC, Yang CH,* 

[14] Ekta Gupta, Meenu Bajpai, Aashish Choudhary. Hepatitis C virus: Screening, diagnosis, and interpretation of laboratory assays. Asian J Transfus

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[15] Fabio Forghieri, Mario Luppi, Patrizia Barozzi, Rossana Maffei, Leonardo Potenza, Franco Narni, and Roberto Marasca. Pathogenetic Mechanisms of Hepatitis C Virus-Induced B-Cell Lymphomagenesis. Clin Dev Immunol. 2012; 2012: 807351.

[16] Siobhán B. Cashman, Brian D.

[17] Maura O'Neil, Ivan Damjanov. Ryan M. Taylor. Basic Hepatopathology:

The Humoral

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2894-2907.

Jack T. Stapleton,

*13(17):2461-6.*

*20(23):7104-22.*

[11] *Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H.* Global epidemiology and genotype distribution of the hepatitis C virus infection.*. J Hepatol. 2014 Nov; 61(1 Suppl):S45-57.*

[2] Dakhil N, Junaidi O, Befeler AS. Chronic viral hepatitis. Mo Med. 2009

[3] *Chen SL, Morgan TR.* The natural history of hepatitis C virus (HCV) infection.*Int J Med Sci. 2006; 3(2):47-52.*

[4] Catelyn Coyle, MPH, MEd, Helena Kwakwa, MD, MPH, Kendra Viner,

Pennsylvania, 2012-2014. Public Health Rep. 2016 May-Jun; 131(Suppl 2): 65-73.

Testing in Primary Care: Lessons Learned from Five Federally Qualified Health Centers in Philadelphia,

[5] Meryem Jefferies, Bisma Rauff, Harunor Rashid, Thao Lam, and Shafquat Rafiq. Update on global epidemiology of viral hepatitis and preventive strategies. World J Clin Cases. 2018 Nov 6; 6(13): 589-599.

[6] Ekta Gupta, Meenu Bajpai, and Aashish Choudhary. Hepatitis C virus: Screening, diagnosis, and interpretation of laboratory assays. Asian J Transfus

[7] Asmaa GomaaNaglaa Allam, Aisha

prevalence, impact and management strategies. Hepat Med. 2017; 9: 17-25.

[8] *Catanese MT, Uryu K, Kopp M, Edwards TJ, Andrus L, Rice WJ, Silvestry M, Kuhn RJ, Rice CM.*

Ultrastructural analysis of hepatitis C virus particles. Proc Natl Acad Sci U S A. 2013 Jun 4; 110(23):9505-10.

[9] Peter Simmonds. Proposed update to the taxonomy of the genera *Hepacivirus*

Mohamed El Kassas, Imam

Hepatitis C infection in Egypt:

Sci. 2014 Jan-Jun; 8(1): 19-25.

Elsharkway,<sup>2</sup>

Waked.

Integrating Routine HCV

Transcription-Mediated Amplification Qualitative Assay. J Clin Microbiol. 2002 Aug; 40(8): 2903-2907.

[32] Adeel A. Butt, Liver Fibrosis Progression in Hepatitis C Virus Infection After Seroconversion. JAMA Intern Med. 2015 Feb; 175(2): 178-185.

[33] Butt AA, Wang X, Moore CM. Effect of HCV and its treatment upon survival. Hepatology. 2009;50(2):387-392.

[34] Julien Massard et al. Natural history and predictors of disease severity in chronic hepatitis C. Journal of Hepatology 44 (2006) S19–S24

[35] Siobhán B. Cashman, Brian D. Marsden, Lynn B. Dustin. The Humoral Immune Response to HCV: Understanding is Key to Vaccine Development. Front Immunol. 2014; 5: 550.

[36] Emmanuel Thomas, Jordan J. Feld,Qisheng Li, Zongyi Hu,Michael W. Fried, T. Jake Liang Ribavirin Potentiates Interferon Action by Augmenting Interferon-Stimulated Gene Induction in Hepatitis C Virus Cell Culture Models. Hepatology. 2011 Jan; 53(1): 32-41.

[37] Shalimar Et al. Hepatitis C Virus Genotype 3: Hope for Nonresponders and Patients With CirrhosisJ Clin Exp Hepatol. 2014 Jun; 4(2): 179-181.

[38] Laure Izquierdo, François Helle, Catherine François, Sandrine Castelain, Gilles Duverlie, Etienne Brochot. **Simeprevir for the treatment of hepatitis C virus infection.** Pharmgenomics Pers Med. 2014; 7: 241-249.

[39] *Toshikuni N, Arisawa T, Tsutsumi M.* Hepatitis C-related liver cirrhosis strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality.*. World J Gastroenterol. 2014 Mar 21; 20(11):2876-87.*

[40] Emilio Palumbo, **Pegylated Interferon and Ribavirin Treatment for Hepatitis C Virus Infection.** Ther Adv Chronic Dis. 2011 Jan; 2(1): 39-45.

[41] Caroline M Perry. Telaprevir: A Review of its Use in the Management of Genotype 1 Chronic Hepatitis . March 2012. Drugs 72(5):619-41

[42] Megan H. Powdrill, Jean A. Bernatchez,Matthias Götte. Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B. Viruses. 2010 Oct; 2(10): 2169-2195.

[43] *Alborino F, Burighel A, Tiller FW, van Helden J, Gabriel C, Raineri A, Catapano R, Stekel H.*Multicenter evaluation of a fully automated third-generation anti-HCV antibody screening test with excellent sensitivity and specificity.*. Med Microbiol Immunol. 2011 May; 200(2):77-83.*

[44] Hideki Fujii, et al. Comparison of peg-interferon, ribavirin plus telaprevir *vs* simeprevir by propensity score matching. World J Hepatol. 2015 Dec 8; 7(28): 2841-2848.

[45] Silvano Wendel. Primary screening of blood donors by nat testing for HCV-RNA: development of an "in-house" method and results. Rev. Inst. Med. trop. S. Paulo vol.49 no.3 São Paulo May/June 2007

**27**

Section 3

Extrahepatic Manifestations

Section 3

## Extrahepatic Manifestations

*Advances in Hepatology*

Aug; 40(8): 2903-2907.

Transcription-Mediated Amplification Qualitative Assay. J Clin Microbiol. 2002 [40] Emilio Palumbo, **Pegylated Interferon and Ribavirin Treatment for Hepatitis C Virus Infection.** Ther Adv Chronic Dis. 2011 Jan; 2(1): 39-45.

[41] Caroline M Perry. Telaprevir: A Review of its Use in the Management of Genotype 1 Chronic Hepatitis . March

2012. Drugs 72(5):619-41

*200(2):77-83.*

7(28): 2841-2848.

2007

[42] Megan H. Powdrill, Jean A. Bernatchez,Matthias Götte. Inhibitors

of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B. Viruses. 2010 Oct; 2(10): 2169-2195.

[43] *Alborino F, Burighel A, Tiller FW, van Helden J, Gabriel C, Raineri A, Catapano R, Stekel H.*Multicenter evaluation of a fully automated third-generation anti-HCV antibody screening test with excellent sensitivity and specificity.*. Med Microbiol Immunol. 2011 May;* 

[44] Hideki Fujii, et al. Comparison of peg-interferon, ribavirin plus telaprevir *vs* simeprevir by propensity score matching. World J Hepatol. 2015 Dec 8;

[45] Silvano Wendel. Primary screening of blood donors by nat testing for HCV-RNA: development of an "in-house" method and results. Rev. Inst. Med. trop. S. Paulo vol.49 no.3 São Paulo May/June

[33] Butt AA, Wang X, Moore CM. Effect of HCV and its treatment upon survival.

[34] Julien Massard et al. Natural history and predictors of disease severity in chronic hepatitis C. Journal of Hepatology 44 (2006) S19–S24

[32] Adeel A. Butt, Liver Fibrosis Progression in Hepatitis C Virus Infection After Seroconversion. JAMA Intern Med. 2015 Feb; 175(2): 178-185.

Hepatology. 2009;50(2):387-392.

[35] Siobhán B. Cashman, Brian D. Marsden, Lynn B. Dustin. The Humoral

Jordan J. Feld,Qisheng Li, Zongyi Hu,Michael W. Fried, T. Jake Liang Ribavirin Potentiates Interferon Action by Augmenting Interferon-Stimulated Gene Induction in Hepatitis C Virus Cell Culture Models. Hepatology. 2011 Jan;

[37] Shalimar Et al. Hepatitis C Virus Genotype 3: Hope for Nonresponders and Patients With CirrhosisJ Clin Exp Hepatol. 2014 Jun; 4(2): 179-181.

**Simeprevir for the treatment** 

[38] Laure Izquierdo, François Helle, Catherine François, Sandrine Castelain, Gilles Duverlie, Etienne

**of hepatitis C virus infection.** Pharmgenomics Pers Med. 2014; 7:

*2014 Mar 21; 20(11):2876-87.*

[39] *Toshikuni N, Arisawa T, Tsutsumi M.* Hepatitis C-related liver cirrhosis strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality.*. World J Gastroenterol.* 

Immune Response to HCV: Understanding is Key to Vaccine Development. Front Immunol. 2014; 5:

[36] Emmanuel Thomas,

550.

53(1): 32-41.

Brochot.

241-249.

**26**

**29**

**1. Introduction**

this area is ongoing [1].

**Chapter 3**

*Alberto Frosi*

**Abstract**

Extrahepatic Manifestations of

Chronic infection with the hepatitis C virus (HCV) is a major cause of liver disease worldwide and is also responsible for extrahepatic manifestations (EHM) involving many different organs and apparatus: skin, salivary glands, eyes, thyroid, kidneys, peripheral and central nervous system, and immune system. Mixed cryoglobulinemia is the most frequent, best known and strictly HCVassociated EHM. A significant association between HCV and B-cell Non-Hodgkin-Lymphoma is reported although the incidence of lymphoma among HCV-infected patients overall remains low. HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular disorders. The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects. Because of this associations, it is suggested testing for HCV infection the patients with a clinical condition described as linked to hepatitis C. Conversely, patients diagnosed with HCV infection should have evaluation for a possible EHM. EHM of HCV can be considered an established indication for antiviral treatment with direct acting antivirals, even in the absence of overt liver disease. Successful eradication of HCV can improve and in some cases cure EHM of HCV. B cell depleting agents may be considered to be the best biological target option for patients with

**Keywords:** HCV, chronic hepatitis C, cryoglobulinemia, B-cell lymphoma, thyroid dysfunction, type 2 diabetes, Sjögren's syndrome, porphyria cutanea tarda, lichen planus, glomerulonephritis, neuropathy, polyarthritis, extrahepatic manifestations

Persistent infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease, resulting in about 400000 deaths per year. The estimated global HCV prevalence is 1.0%, corresponding to 71 million individuals. Antiviral medicines can cure more than 95% of persons with hepatitis C infection, thereby reducing the risk of death from cirrhosis and liver cancer, but access to diagnosis and treatment is low. There is currently no effective vaccine against hepatitis C; however, research in

However, these data are underestimated do not taking into account the extrahepatic aspects that make this infection a systemic disease. Early after its discovery, it was shown that HCV is not only hepatotropic but also lymphotropic. It was also shown that several extrahepatic manifestations (EHM) can complicate HCV infection [2–4].

Hepatitis C Infection

more severe EHM in combination with the antivirals.

#### **Chapter 3**

## Extrahepatic Manifestations of Hepatitis C Infection

*Alberto Frosi*

#### **Abstract**

Chronic infection with the hepatitis C virus (HCV) is a major cause of liver disease worldwide and is also responsible for extrahepatic manifestations (EHM) involving many different organs and apparatus: skin, salivary glands, eyes, thyroid, kidneys, peripheral and central nervous system, and immune system. Mixed cryoglobulinemia is the most frequent, best known and strictly HCVassociated EHM. A significant association between HCV and B-cell Non-Hodgkin-Lymphoma is reported although the incidence of lymphoma among HCV-infected patients overall remains low. HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular disorders. The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects. Because of this associations, it is suggested testing for HCV infection the patients with a clinical condition described as linked to hepatitis C. Conversely, patients diagnosed with HCV infection should have evaluation for a possible EHM. EHM of HCV can be considered an established indication for antiviral treatment with direct acting antivirals, even in the absence of overt liver disease. Successful eradication of HCV can improve and in some cases cure EHM of HCV. B cell depleting agents may be considered to be the best biological target option for patients with more severe EHM in combination with the antivirals.

**Keywords:** HCV, chronic hepatitis C, cryoglobulinemia, B-cell lymphoma, thyroid dysfunction, type 2 diabetes, Sjögren's syndrome, porphyria cutanea tarda, lichen planus, glomerulonephritis, neuropathy, polyarthritis, extrahepatic manifestations

#### **1. Introduction**

Persistent infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease, resulting in about 400000 deaths per year. The estimated global HCV prevalence is 1.0%, corresponding to 71 million individuals. Antiviral medicines can cure more than 95% of persons with hepatitis C infection, thereby reducing the risk of death from cirrhosis and liver cancer, but access to diagnosis and treatment is low. There is currently no effective vaccine against hepatitis C; however, research in this area is ongoing [1].

However, these data are underestimated do not taking into account the extrahepatic aspects that make this infection a systemic disease. Early after its discovery, it was shown that HCV is not only hepatotropic but also lymphotropic. It was also shown that several extrahepatic manifestations (EHM) can complicate HCV infection [2–4].

#### **Figure 1.**

*The spectrum of extrahepatic manifestations of HCV [6].*

Moreover, chronic HCV infection has been associated with numerous EHM and diseases, although a direct link is often difficult to establish.

Association should not be confused with causality. The association merely suggests a hypothesis, such as a common cause, but does not offer proof [5].

A causal relationship is easily acceptable if the strength of association is hight. Furthermore, according to the criterion of plausibility, the association ought to be biologically plausible.

The EHM described as linked to HCV hepatitis are numerous:

Mixed cryoglobulinemia (MC), sicca syndrome (SS), Non-Hodgkin Lymphoma (NHL), serum monoclonal gammopathy, thyroid disease, type 2 diabetes mellitus and glucose intolerance, many autoimmune disorders, renal disease, rheumatologic, neurological, cardiovascular and dermatological disorders [6] (**Figure 1**).

Here are described the most clinical important and best studied of these pathological conditions.

#### **2. Biological plausibility and pathophysiology**

The pathophysiology of EHM of HCV hepatitis is only in part understood and for some of them unexplained.

The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects.

Due to the fact that HCV has been shown to infect both hepatocytes and lymphocytes, lymphoproliferative diseases such as lymphoma and MC are most closely linked to hepatitis C infection. These conditions are the most studied from the point of view of their pathophysiology. The primary mechanism of injury in cryoglobulinemia is a vasculitis triggered by immune complex deposition.

HCV has been shown to be a lymphotropic virus and associated with several lymphoproliferative disorders, including monoclonal gammopathies in addition to

**31**

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

malignant transformation were described.

mechanisms of pathogenesis.

nerve damage.

which were identified in HCV-associated B-cell lymphomas.

reported to contribute to aberrant B-cell proliferation.

between viral antigens and thyroidal antigens.

among HCV-infected patients overall remains low.

immune responses [2–4, 6, 7].

**3. Mixed cryoglobulinemia**

is a further possible mechanism of HCV-related glomerular injury.

MC and B-cell NHL. HCV infection of lymphocytes could play a direct role in cellular transformation, specifically in de novo large B-cell lymphoma. HCV infection of two B-cell lines can produce mutations in tumor suppressor and proto-oncogenes

Two particulars although not mutually exclusive models of infection-driven

Expression of HCV viral proteins in B-cells of HCV-infected patients upregulates

Glomerular injury in HCV-related glomerulonephritis is primary induced by a deposition of circulating immunocomplexes containing anti-HCV antibodies, HCV antigens and complement factors. Formation and deposition of such immunocomplexes occurs also in absence of cryoglobulins. Formation of glomerular antibodies

Peripheral nerves of patients with HCV-related peripheral neuropathy may show vasculitic changes involving the vasa nervorum, giving a possible explanation of

Studies have shown that dysthyroidism is mediated by immunological mechanisms rather than by direct HCV infection. The pathogenesis may involve changes in self-antigen expression and sustained stimulation of the immune system by HCV, bystander activation of autoreactive T-cells by cytokine release, infection of the lymphatic cells, chromosomal aberrations and abnormal expression of major histocompatibility complex class II molecules by thyrocytes, or cross-reactivity

Primary causation of dermatological EHM (apart the cryoglobulinaemic ones) results from direct infection of HCV in the skin, lymphocytes, dendritic antigenpresenting cells, and blood vessels. Secondary causation occurs when HCV infection manifests in the skin due to epiphenomena resulting from the disruption of

The most common extrahepatic findings with which the relationship to HCV infection is more strongly established are cryoglobulinemia, autoimmune disorders (including autoantibodies and SS), porphyria cutanea tarda (PCT), and lichen planus (LP). There also appears to be a clear association with B-cell NHL (particularly in patients with underlying cryoglobulinemia), but the incidence of lymphoma

MC is the most frequent, best known and strictly HCV-associated EHM (about

The definition of MC refers to the presence of serum Igs that reversibly precipitate at low temperatures (<37°C) and are represented by circulating immune

90% of MC patients tested positive for HCV antibodies in some studies) [7, 8]. MC may be defined a both autoimmune and B-lymphoproliferative disorder

(LPD) that may evolve to a frank malignancy in about 8–10% of cases [9].

B-cell receptor signaling. Pro-inflammatory cytokines, such as the interleukins (IL-6, IL-17 and IL-10) and transforming growth factor-beta have also been

Direct lymphocyte transformation by lymphotropic transforming viruses (Epstein–Barr virus, human herpesvirus, and human T-lymphotropic virus type) expressing viral oncogenes has been reported. A model of lymphocyte transformation finally leading to clonal expansion as an indirect mechanism of pathogenesis has been proposed. Sustained stimulation of lymphocyte receptors by viral antigens, viral replication in B-cells, and damage of B-cells have been also proposed as

#### *Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

*Advances in Hepatology*

biologically plausible.

**Figure 1.**

pathological conditions.

for some of them unexplained.

Moreover, chronic HCV infection has been associated with numerous EHM and

Association should not be confused with causality. The association merely suggests

A causal relationship is easily acceptable if the strength of association is hight. Furthermore, according to the criterion of plausibility, the association ought to be

Mixed cryoglobulinemia (MC), sicca syndrome (SS), Non-Hodgkin Lymphoma (NHL), serum monoclonal gammopathy, thyroid disease, type 2 diabetes mellitus and glucose intolerance, many autoimmune disorders, renal disease, rheumatologic,

The pathophysiology of EHM of HCV hepatitis is only in part understood and

The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic

Due to the fact that HCV has been shown to infect both hepatocytes and lymphocytes, lymphoproliferative diseases such as lymphoma and MC are most closely linked to hepatitis C infection. These conditions are the most studied from the point of view of their pathophysiology. The primary mechanism of injury in cryoglobuli-

HCV has been shown to be a lymphotropic virus and associated with several lymphoproliferative disorders, including monoclonal gammopathies in addition to

diseases, although a direct link is often difficult to establish.

*The spectrum of extrahepatic manifestations of HCV [6].*

**2. Biological plausibility and pathophysiology**

cells, or a heightened immune reaction with systemic effects.

nemia is a vasculitis triggered by immune complex deposition.

a hypothesis, such as a common cause, but does not offer proof [5].

The EHM described as linked to HCV hepatitis are numerous:

neurological, cardiovascular and dermatological disorders [6] (**Figure 1**). Here are described the most clinical important and best studied of these

**30**

MC and B-cell NHL. HCV infection of lymphocytes could play a direct role in cellular transformation, specifically in de novo large B-cell lymphoma. HCV infection of two B-cell lines can produce mutations in tumor suppressor and proto-oncogenes which were identified in HCV-associated B-cell lymphomas.

Two particulars although not mutually exclusive models of infection-driven malignant transformation were described.

Direct lymphocyte transformation by lymphotropic transforming viruses (Epstein–Barr virus, human herpesvirus, and human T-lymphotropic virus type) expressing viral oncogenes has been reported. A model of lymphocyte transformation finally leading to clonal expansion as an indirect mechanism of pathogenesis has been proposed. Sustained stimulation of lymphocyte receptors by viral antigens, viral replication in B-cells, and damage of B-cells have been also proposed as mechanisms of pathogenesis.

Expression of HCV viral proteins in B-cells of HCV-infected patients upregulates B-cell receptor signaling. Pro-inflammatory cytokines, such as the interleukins (IL-6, IL-17 and IL-10) and transforming growth factor-beta have also been reported to contribute to aberrant B-cell proliferation.

Glomerular injury in HCV-related glomerulonephritis is primary induced by a deposition of circulating immunocomplexes containing anti-HCV antibodies, HCV antigens and complement factors. Formation and deposition of such immunocomplexes occurs also in absence of cryoglobulins. Formation of glomerular antibodies is a further possible mechanism of HCV-related glomerular injury.

Peripheral nerves of patients with HCV-related peripheral neuropathy may show vasculitic changes involving the vasa nervorum, giving a possible explanation of nerve damage.

Studies have shown that dysthyroidism is mediated by immunological mechanisms rather than by direct HCV infection. The pathogenesis may involve changes in self-antigen expression and sustained stimulation of the immune system by HCV, bystander activation of autoreactive T-cells by cytokine release, infection of the lymphatic cells, chromosomal aberrations and abnormal expression of major histocompatibility complex class II molecules by thyrocytes, or cross-reactivity between viral antigens and thyroidal antigens.

Primary causation of dermatological EHM (apart the cryoglobulinaemic ones) results from direct infection of HCV in the skin, lymphocytes, dendritic antigenpresenting cells, and blood vessels. Secondary causation occurs when HCV infection manifests in the skin due to epiphenomena resulting from the disruption of immune responses [2–4, 6, 7].

The most common extrahepatic findings with which the relationship to HCV infection is more strongly established are cryoglobulinemia, autoimmune disorders (including autoantibodies and SS), porphyria cutanea tarda (PCT), and lichen planus (LP). There also appears to be a clear association with B-cell NHL (particularly in patients with underlying cryoglobulinemia), but the incidence of lymphoma among HCV-infected patients overall remains low.

#### **3. Mixed cryoglobulinemia**

MC is the most frequent, best known and strictly HCV-associated EHM (about 90% of MC patients tested positive for HCV antibodies in some studies) [7, 8].

MC may be defined a both autoimmune and B-lymphoproliferative disorder (LPD) that may evolve to a frank malignancy in about 8–10% of cases [9].

The definition of MC refers to the presence of serum Igs that reversibly precipitate at low temperatures (<37°C) and are represented by circulating immune complex typically consisting of an IgM rheumatoid factor (mono-oligoclonal in type II MC, or polyclonal in type III MC) and polyclonal Ig (most frequently IgG) including anti-HCV antibodies. MC has been generally reported, at least subclinical, in the majority of HCV patients, even if data may widely vary in different geographical areas (from 20 to >50%). Only a minority of MC patients (5 to >30%) shows a symptomatic MC or MC syndrome (usually women aged more than 50 years), but even asymptomatic patients might develop MC in the future [10].

Factors that seem to favor the development of MC are female sex, increasing age, alcohol consumption (> 50 g/day), advanced liver fibrosis and steatosis.

The clinical manifestations of MC are secondary to a systemic vasculitis characterized by the deposition of cryoglobulins in the vessels and can be classified as one of the circulating immune complexes mediated systemic vasculitis involving small and medium-sized blood vessels.

The classic syndrome of MC consists in the triad of purpura, fatigue and arthralgia, but the various involvement of different organs and tissues (mainly skin, joints, renal, peripheral nerves) leads to variable clinical presentation and evolution.

Palpable purpura (leukocytoclastic vasculitis) and petechiae most often affects the legs (**Figure 2**).

Papules, ulcers, and livedo can also occur and can affect any skin site.

Reynaud Syndrome can be present, with or without digital gangrene, in about one third of patients.

**33**

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

(MPGN), and neurologic disease.

observed (15% of cases).

than in type III MC [2, 4].

severe liver damage [11].

**5.1 Non-Hodgkin lymphoma**

large B-cell lymphoma.

for MC).

below 9.).

and pruritus.

(see below 9).

Common manifestations of MC are arthralgias (polyarthralgia, but relatively rare is arthritis), renal disease, usually membranoproliferative glomerulonephritis

MPGN is characterized in most cases by proteinuria, mild haematuria and mild renal insufficiency. In the worst cases, a severe involvement of the kidney is

The peripheral neuropathy including mixed neuropathies (prevalently sensitive, axonal) is common in MC (80–90% of cases), and also in HCV without MC (see

HCV-related peripheral neuropathy is characterized by numbness, burning skin

Central nervous system involvement in patients with HCV-positive MC is rare

SjÖgren syndrome is described as a chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and B-lymphocyte reactivity resulting in xerostomia and dry eyes. SS, to be differentiated from the primary SjÖgren Syndrome, occurs in MC and also in HCV patients without MC [2–4]. In most instances the typical serological and histopathologic findings of SjÖgren Syndrome are lacking. SS is more frequently reported in type II

Some studies showed an association between MC in HCV infected patients and

However, discordant data exist. It is common clinical experience, including our own, to find patients with symptomatic HCV-related MC and a mild or moderate liver disease and conversely patients with the most severe form of chronic hepatitis C (advanced fibrosis, compensated and decompensated cirrhosis, hepatocellular carcinoma) without any symptom of MC (even when laboratory testing positive

The very close association between MC and HCV infection leads to the hypothesis

A significant association between HCV and B-cell NHL was reported and

This association involves different histopathological types of B-cell NHL, the most strictly associated being the lymphoplasmacytic, marginal zone and diffuse

Some discordant data suggested the contribution of genetic factors and the incidence of lymphoma among HCV-infected patients overall remains low.

Although the difference was statistically significant (P < 0.001), the odds ratio was 2.049 and its confidence intervals included the equality. NHL features

In an observational, prospective, multicenter, case–control study, the prevalence of HCV-antibodies was found of 0.16 among NHL and of 0.085 among controls and

**5. Non-Hodgkin lymphoma and other hematological disorders**

that HCV may be involved in the pathogenesis of lymphoma as well.

confirmed in the large majority of studies [12].

non-lymphoid malignancies patients [13].

**4. Sicca syndrome (secondary SjÖgren syndrome)**

**Figure 2.** *Cutaneous manifestation of mixed cryoglobulinemia (see text).*

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

*Advances in Hepatology*

future [10].

and medium-sized blood vessels.

the legs (**Figure 2**).

one third of patients.

complex typically consisting of an IgM rheumatoid factor (mono-oligoclonal in type II MC, or polyclonal in type III MC) and polyclonal Ig (most frequently IgG) including anti-HCV antibodies. MC has been generally reported, at least subclinical, in the majority of HCV patients, even if data may widely vary in different geographical areas (from 20 to >50%). Only a minority of MC patients (5 to >30%) shows a symptomatic MC or MC syndrome (usually women aged more than 50 years), but even asymptomatic patients might develop MC in the

Factors that seem to favor the development of MC are female sex, increasing age,

The clinical manifestations of MC are secondary to a systemic vasculitis characterized by the deposition of cryoglobulins in the vessels and can be classified as one of the circulating immune complexes mediated systemic vasculitis involving small

The classic syndrome of MC consists in the triad of purpura, fatigue and arthralgia, but the various involvement of different organs and tissues (mainly skin, joints, renal, peripheral nerves) leads to variable clinical presentation and evolution.

Palpable purpura (leukocytoclastic vasculitis) and petechiae most often affects

Reynaud Syndrome can be present, with or without digital gangrene, in about

Papules, ulcers, and livedo can also occur and can affect any skin site.

alcohol consumption (> 50 g/day), advanced liver fibrosis and steatosis.

**32**

**Figure 2.**

*Cutaneous manifestation of mixed cryoglobulinemia (see text).*

Common manifestations of MC are arthralgias (polyarthralgia, but relatively rare is arthritis), renal disease, usually membranoproliferative glomerulonephritis (MPGN), and neurologic disease.

MPGN is characterized in most cases by proteinuria, mild haematuria and mild renal insufficiency. In the worst cases, a severe involvement of the kidney is observed (15% of cases).

The peripheral neuropathy including mixed neuropathies (prevalently sensitive, axonal) is common in MC (80–90% of cases), and also in HCV without MC (see below 9.).

HCV-related peripheral neuropathy is characterized by numbness, burning skin and pruritus.

Central nervous system involvement in patients with HCV-positive MC is rare (see below 9).

#### **4. Sicca syndrome (secondary SjÖgren syndrome)**

SjÖgren syndrome is described as a chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and B-lymphocyte reactivity resulting in xerostomia and dry eyes. SS, to be differentiated from the primary SjÖgren Syndrome, occurs in MC and also in HCV patients without MC [2–4]. In most instances the typical serological and histopathologic findings of SjÖgren Syndrome are lacking. SS is more frequently reported in type II than in type III MC [2, 4].

Some studies showed an association between MC in HCV infected patients and severe liver damage [11].

However, discordant data exist. It is common clinical experience, including our own, to find patients with symptomatic HCV-related MC and a mild or moderate liver disease and conversely patients with the most severe form of chronic hepatitis C (advanced fibrosis, compensated and decompensated cirrhosis, hepatocellular carcinoma) without any symptom of MC (even when laboratory testing positive for MC).

#### **5. Non-Hodgkin lymphoma and other hematological disorders**

#### **5.1 Non-Hodgkin lymphoma**

The very close association between MC and HCV infection leads to the hypothesis that HCV may be involved in the pathogenesis of lymphoma as well.

A significant association between HCV and B-cell NHL was reported and confirmed in the large majority of studies [12].

This association involves different histopathological types of B-cell NHL, the most strictly associated being the lymphoplasmacytic, marginal zone and diffuse large B-cell lymphoma.

Some discordant data suggested the contribution of genetic factors and the incidence of lymphoma among HCV-infected patients overall remains low.

In an observational, prospective, multicenter, case–control study, the prevalence of HCV-antibodies was found of 0.16 among NHL and of 0.085 among controls and non-lymphoid malignancies patients [13].

Although the difference was statistically significant (P < 0.001), the odds ratio was 2.049 and its confidence intervals included the equality. NHL features


*Lower confidence limit below. b WF classification is available for 293.*

#### **Table 1.**

*NHL features among HCV-positive and HCV-negative patients [13].*

among HCV-positive and HCV-negative patients observed in this study are reported in the **Table 1**.

#### **5.2 Serum monoclonal gammopathy and thrombocytopenia**

A serum monoclonal gammopathy (MG), more frequently type IgMk and diagnosed as MG of uncertain significance (MGUS), was frequently observed in HCV patients, in most cases associated with a 2a/c genotype of the virus.

Available data suggest that HCV-related LPD are the result of multiple and cooperating mechanisms and events belonging to three principal categories: an important and sustained activation of the B-cell compartment; an inhibition of B-cell apoptosis; genetic/epigenetic and environmental factors (see also above 2.).

Thrombocytopenia is often observed in patients with chronic HCV hepatitis and sometimes it is disproportionally severe with respect of the stage of fibrosis-cirrhosis.

It is possible recognize as causal factors of thrombocytopenia in HCV chronic hepatitis the following: decrease of hepatic thrombopoietin, direct cytopathic involvement of HCV on megakaryocytes, production of platelets-associated immunoglobulins, hypersplenism.

#### **6. Endocrine pathology and hepatitis C virus infection**

#### **6.1 Thyroid disease**

The prevalence of thyroid disorders is generally high in HCV-positive patients and most frequently represented by antithyroid peroxidase antibodies

**35**

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

in 30–70% of HCV patients [3, 15].

impaired glucose tolerance.

**7.1 Autoantibodies**

infection.

difficulties.

diagnostically.

different.

**7.2 Rheumatologic disorders**

are generally absent [2].

**6.2 Type 2 diabetes mellitus and glucose intolerance**

**7. Autoimmune and rheumatologic disorders**

rare cases the two disease coexist in the same patient.

shown [14].

in female subjects. Hypothyroidism has been frequently observed, especially in HCV MC, and an association with papillary thyroid carcinoma was also

Several studies showed that HCV (especially genotype 3) could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. However, discordant data exist. Insulin resistance was observed

The cause of the association of HCV with diabetes is unknown. In addition, the magnitude of the association may be overestimated because patients with diabetes have more parenteral exposures than the general population, placing them at increased risk for transmission of blood transmitted viruses. Furthermore, not all studies controlled for the presence of cirrhosis, which may be associated with

A number of autoimmune disorders have been associated with chronic HCV infection, including subclinical autoantibody formation, autoimmune thyroid

disease, sialadenitis/SS, and autoimmune thrombocytopenic purpura. Autoantibodies are common in patients with chronic HCV infection. Antinuclear antibodies, antibodies directed against the Fc portion of IgG (rheumatoid factor), anticardiolipin antibodies, smooth muscle antibodies, or antithyroid antibodies are detected in 40 to 65 percent of patients. While antibodies are often present in low titres, do not appear to influence the presentation or course of the

Nevertheless, the presence of autoantibodies may result in diagnostic

For example, an HCV-infected patient with arthralgias, arthritis, and rheumatoid factor positivity may be misdiagnosed initially as having rheumatoid arthritis. In this setting, testing for other rheumatoid-arthritis-associated autoantibodies that are observed infrequently in patients with HCV infection, such as anti-citrullinated peptide antibodies (anti-CCP), may be helpful

In other cases, a difficult differential diagnosis between hepatitis C and autoimmune hepatitis can rise. In these cases, the liver biopsy findings are decisive. In

Making a precise diagnosis is crucial because the treatment is completely

Polyarthralgia is the most common rheumatologic symptom described in HCV-infected patients. HCV arthritis could be part of the MC or be independent. HCV-associated oligoarticular or polyarticular non-erosive arthritis can clinically mimic rheumatoid arthritis, although anti-CCP antibodies and erosive joint changes in female subjects. Hypothyroidism has been frequently observed, especially in HCV MC, and an association with papillary thyroid carcinoma was also shown [14].

#### **6.2 Type 2 diabetes mellitus and glucose intolerance**

Several studies showed that HCV (especially genotype 3) could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. However, discordant data exist. Insulin resistance was observed in 30–70% of HCV patients [3, 15].

The cause of the association of HCV with diabetes is unknown. In addition, the magnitude of the association may be overestimated because patients with diabetes have more parenteral exposures than the general population, placing them at increased risk for transmission of blood transmitted viruses. Furthermore, not all studies controlled for the presence of cirrhosis, which may be associated with impaired glucose tolerance.

#### **7. Autoimmune and rheumatologic disorders**

#### **7.1 Autoantibodies**

*Advances in Hepatology*

**Feature (overall freq.) HCV-positive** 

**NHL (48)**

**Bearing feature**

**HCV-negative NHL (252)**

**Bearing feature**

**Freq. (conf. Int. 95%)**

**Freq. (conf. Int. 95%)**

(0.286) 14 0.304 (0.071–0.437) 70 0.283 (0.227–0.339)

(0.248) 10 0.217 (0.098–0.336) 63 0.255 (0.201–0.309)

MALT (0.053) 3 0.062a 13 0.052 (0.022–0.088)

(0.464) 22 0.478 (0.334–0.622) 114 0.462 (0.400–0.524)

Extranodal inv. (0.593) 30 0.625 (0.488–0.762) 148 0.587 (0.526–0.648) Marrow inv. (0.283) 16 0.333 (0.200–0.466) 69 0.274 (0.219–0.329) Stomach inv. (0.067) 2 0.042a 18 0.071 (0.039–0.103) Liver inv. (0.030) 4 0.083 (0.005–0.161) 5 0.020 (0.003–0.037) Cryoglobulinis (0.033) 3 0.063a 7 0.028 (0.026–0.030) Age to 20 (0.007) 0 0 2 0.008a Age 21–40 (0.090) 2 0.042a 25 0.099 (0.062–0.136) Age 41–60 (0.300) 12 0.250 (0.128–0.372) 78 0.310 (0.253–0.367) Age > 60 (0.603) 34 0.708 (0.579–0.837) 147 0.583 (0.522–0.643)

reported in the **Table 1**.

*Lower confidence limit below.*

*WF classification is available for 293.*

WF A, B, Cb

WF D, E, Fb

*a*

*b*

**Table 1.**

WF G, H, I, Jb

fibrosis-cirrhosis.

**6.1 Thyroid disease**

immunoglobulins, hypersplenism.

among HCV-positive and HCV-negative patients observed in this study are

A serum monoclonal gammopathy (MG), more frequently type IgMk and diagnosed as MG of uncertain significance (MGUS), was frequently observed in HCV

Available data suggest that HCV-related LPD are the result of multiple and cooperating mechanisms and events belonging to three principal categories: an important and sustained activation of the B-cell compartment; an inhibition of B-cell apoptosis; genetic/epigenetic and environmental factors (see also above 2.). Thrombocytopenia is often observed in patients with chronic HCV hepatitis and sometimes it is disproportionally severe with respect of the stage of

It is possible recognize as causal factors of thrombocytopenia in HCV chronic hepatitis the following: decrease of hepatic thrombopoietin, direct cytopathic involvement of HCV on megakaryocytes, production of platelets-associated

The prevalence of thyroid disorders is generally high in HCV-positive patients and most frequently represented by antithyroid peroxidase antibodies

**5.2 Serum monoclonal gammopathy and thrombocytopenia**

*NHL features among HCV-positive and HCV-negative patients [13].*

patients, in most cases associated with a 2a/c genotype of the virus.

**6. Endocrine pathology and hepatitis C virus infection**

**34**

A number of autoimmune disorders have been associated with chronic HCV infection, including subclinical autoantibody formation, autoimmune thyroid disease, sialadenitis/SS, and autoimmune thrombocytopenic purpura.

Autoantibodies are common in patients with chronic HCV infection. Antinuclear antibodies, antibodies directed against the Fc portion of IgG (rheumatoid factor), anticardiolipin antibodies, smooth muscle antibodies, or antithyroid antibodies are detected in 40 to 65 percent of patients. While antibodies are often present in low titres, do not appear to influence the presentation or course of the infection.

Nevertheless, the presence of autoantibodies may result in diagnostic difficulties.

For example, an HCV-infected patient with arthralgias, arthritis, and rheumatoid factor positivity may be misdiagnosed initially as having rheumatoid arthritis. In this setting, testing for other rheumatoid-arthritis-associated autoantibodies that are observed infrequently in patients with HCV infection, such as anti-citrullinated peptide antibodies (anti-CCP), may be helpful diagnostically.

In other cases, a difficult differential diagnosis between hepatitis C and autoimmune hepatitis can rise. In these cases, the liver biopsy findings are decisive. In rare cases the two disease coexist in the same patient.

Making a precise diagnosis is crucial because the treatment is completely different.

#### **7.2 Rheumatologic disorders**

Polyarthralgia is the most common rheumatologic symptom described in HCV-infected patients. HCV arthritis could be part of the MC or be independent. HCV-associated oligoarticular or polyarticular non-erosive arthritis can clinically mimic rheumatoid arthritis, although anti-CCP antibodies and erosive joint changes are generally absent [2].

#### **8. Renal disease**

Several renal manifestations have been associated with HCV infection, the most common being MPGN. HCV-associated membranous or proliferative glomerulonephritis or focal segmental glomerulosclerosis have been also described. The strongest association was reported for cryoglobulinaemic MPGN. Microhaematuria and proteinuria are the most frequent clinical findings of MPGN. The presence of a renal involvement is one of the worst prognostic indices in the natural history of MC [16].

### **9. Neurological disorders**

Peripheral neuropathy: see above, in the context of MC. Less frequently, peripheral neuropathy can be present without MC. Peripheral neuropathy can be sensory or sensorimotor.

Symptoms of fatigue and deficits in concentration and working memory are commonly reported in patients with chronic HCV infection. Some studies have suggested neurocognitive impairments associated with HCV, even after controlling for other comorbid conditions, such as substance abuse, affective disorders, and cirrhosis. Functional imaging studies have also identified metabolic changes in the central nervous system in the setting of HCV infection (not ascribable to hepatic encephalopathy) [3].

### **10. Dermatological manifestations**

Apart the dermatological manifestations of MC (see above 3.) the are other dermatological conditions associated with HCV infection deserving to be discussed.

#### **10.1 Lichen planus**

Cutaneous LP is characterized by flat-topped, pink to violaceous, pruritic papules with a potentially generalized distribution. The papules appear

**37**

**Figure 4.**

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

involve mucus membranes, hair, and nails.

10 to 40%.

findings.

liver disease.

**10.2 Porphyria cutanea tarda**

HCV infection in the general population.

*Typical cutaneous manifestations of porphyria cutanea tarda (see text).*

polygonal-shaped, translucent under incident light. They are 2–4 mm in diameter, with irregular margins and a hard-elastic consistency (**Figure 3**). LP can also

HCV infection has been reported frequently among patients with LP. In some studies, the prevalence of anti-HCV antibodies in patients with LP ranges from

Systematic reviews have reported that patients with oral LP planus are approximately two to six times more likely to have reactive anti-HCV antibodies compared with controls, although there is substantial geographical heterogeneity to the

LP can be seen in patients with a variety of liver diseases, particularly advanced

There is evidence of a genetic risk for HCV-associated LP. The most commonly

PCT is a disease caused by reduced activity of the enzyme uroporphyrinogen decarboxylase (UROD), causing the subsequent build-up of uroporphyrinogen in the blood and urine. PCT has both sporadic and inherited (autosomal dominant) forms that are indistinguishable clinically. A strong association between the sporadic form of PCT and HCV infection has been demonstrated in multiple studies (an overall prevalence of HCV of 50%). However, there was marked geographic variability; lowest prevalence rates (20 to 30%) were observed in reports from Australia, the Czech Republic, and France, while the highest rates (71 to 85%) were observed in Japan, Italy, and Spain. The prevalence in North America was 66%.

A central factor in the geographic variability appeared to be the baseline rates of

The skin and the liver are the two main sites affected in sporadic PCT. Skin disease is characterized by photosensitivity and skin fragility, with which exposure

used drugs in cutaneous LP are topical and systemic corticosteroids, for their

immunosuppressive and anti-inflammatory effects [4, 17, 18].

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

*Advances in Hepatology*

**8. Renal disease**

**9. Neurological disorders**

sensory or sensorimotor.

encephalopathy) [3].

**10.1 Lichen planus**

**10. Dermatological manifestations**

**36**

**Figure 3.**

*Typical manifestation of lichen planus of the volar distal forearm and wrist in a hepatitis C patient (see text).*

Several renal manifestations have been associated with HCV infection, the most common being MPGN. HCV-associated membranous or proliferative glomerulonephritis or focal segmental glomerulosclerosis have been also described. The strongest association was reported for cryoglobulinaemic MPGN. Microhaematuria and proteinuria are the most frequent clinical findings of MPGN. The presence of a renal involvement is one of the worst prognostic indices in the natural history of MC [16].

Peripheral neuropathy: see above, in the context of MC. Less frequently, peripheral neuropathy can be present without MC. Peripheral neuropathy can be

Symptoms of fatigue and deficits in concentration and working memory are commonly reported in patients with chronic HCV infection. Some studies have suggested neurocognitive impairments associated with HCV, even after controlling for other comorbid conditions, such as substance abuse, affective disorders, and cirrhosis. Functional imaging studies have also identified metabolic changes in the central nervous system in the setting of HCV infection (not ascribable to hepatic

Apart the dermatological manifestations of MC (see above 3.) the are other dermatological conditions associated with HCV infection deserving to be discussed.

Cutaneous LP is characterized by flat-topped, pink to violaceous, pruritic papules with a potentially generalized distribution. The papules appear polygonal-shaped, translucent under incident light. They are 2–4 mm in diameter, with irregular margins and a hard-elastic consistency (**Figure 3**). LP can also involve mucus membranes, hair, and nails.

HCV infection has been reported frequently among patients with LP. In some studies, the prevalence of anti-HCV antibodies in patients with LP ranges from 10 to 40%.

Systematic reviews have reported that patients with oral LP planus are approximately two to six times more likely to have reactive anti-HCV antibodies compared with controls, although there is substantial geographical heterogeneity to the findings.

LP can be seen in patients with a variety of liver diseases, particularly advanced liver disease.

There is evidence of a genetic risk for HCV-associated LP. The most commonly used drugs in cutaneous LP are topical and systemic corticosteroids, for their immunosuppressive and anti-inflammatory effects [4, 17, 18].

#### **10.2 Porphyria cutanea tarda**

PCT is a disease caused by reduced activity of the enzyme uroporphyrinogen decarboxylase (UROD), causing the subsequent build-up of uroporphyrinogen in the blood and urine. PCT has both sporadic and inherited (autosomal dominant) forms that are indistinguishable clinically. A strong association between the sporadic form of PCT and HCV infection has been demonstrated in multiple studies (an overall prevalence of HCV of 50%). However, there was marked geographic variability; lowest prevalence rates (20 to 30%) were observed in reports from Australia, the Czech Republic, and France, while the highest rates (71 to 85%) were observed in Japan, Italy, and Spain. The prevalence in North America was 66%.

A central factor in the geographic variability appeared to be the baseline rates of HCV infection in the general population.

The skin and the liver are the two main sites affected in sporadic PCT. Skin disease is characterized by photosensitivity and skin fragility, with which exposure

**Figure 4.** *Typical cutaneous manifestations of porphyria cutanea tarda (see text).*

to the sun and/or minor trauma can lead to skin erythema and the development of vesicles and bullae that may become haemorrhagic.

Hyperpigmentation, hypopigmentation, hirsutism, and sclerodermatous changes may develop with the passage of time (**Figure 4**).

Chronic liver disease is common in sporadic PCT. Liver biopsy shows a wide range of changes, including steatosis, mild to severe inflammation, hepatic fibrosis, and cirrhosis. Environmental triggers are thought to be necessary to provoke an attack of PCT. Possible triggers of PCT include polyhalogenated hydrocarbons (such as hexachlorobenzene), oestrogens, but above all, iron overload and alcoholic beverages. The diagnosis of PCT is typically suspected on clinical grounds and is confirmed by the demonstration of markedly elevated urine uroporphyrin levels. The diagnosis can also be made directly by measuring hepatic UROD activity. All patients with PCT should be tested for HCV infection, as well as other potential disease associations, including HIV infection, iron overload, and hemochromatosis (with HFE mutation testing). Careful history of alcohol intake and testing of heavy alcohol intake markers are fundamental.

Management of PCT in patients with HCV infection includes avoiding precipitating factors (such as sun, alcohol, oestrogens, and polyhalogenated hydrocarbons), treating an underlying iron overload state, if present, and treating HCV infection.

PCT often, but not always, improves with clearance of HCV viremia. The currently used pharmacological protocol for PCT include the administration of a half tablet of chloroquine (125 mg) twice a week [19, 20].

#### **11. Cardiovascular and respiratory diseases**

Although data from individual cohorts have not been consistent, evidence overall suggests that chronic HCV infection is associated with adverse cardiovascular diseases and outcomes: dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, myocarditis, and aortic atherosclerosis. These associations are still object of debate. Because cardiovascular diseases are common and multifactorial, it is difficult to determine whether HCV is a major contributing factor in an individual patient [3].

Idiopathic pulmonary fibrosis is a serious condition described in association with HCV infection.

#### **12. Clinical implications and laboratory tests**

Because of the associations, it is suggested testing for HCV infection in patients with clinical condition described above and other suspected to be linked to HCV. Anti-HCV antibodies (an inexpensive test) must be checked and if positive, quantitative HCV-RNA, genotype and complete workup of hepatitis C performed.

Conversely, patients diagnosed with chronic HCV infection should have evaluation for EHM at the initial visit and routinely during follow-up. History of an HCVinfected patient should cover rheumatologic symptoms (e.g., arthritis/arthralgias, dry eyes or mouth) and the physical exam should include a skin exam to evaluate for findings of cryoglobulinemia, PCT, and other associated dermatologic features. Superficial lymph node sites must be checked. Abdominal ultrasound is part of the HCV patient evaluation. It is in addiction necessary to perform a chest x-ray with particular attention to the mediastinum.

**39**

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

**13.1 Antiviral treatment**

analogues) and NS5A protein.

cutaneous EHM of HCV hepatitis.

tional guidelines.

patients with SVR.

chemotherapy/rituximab.

therapeutic approach in HCV-related EHM [21].

the risk of death from cirrhosis and liver cancer.

therapies for HCV hepatitis must be considered obsolete.

be guided by symptoms or specific physical findings.

without any pancreatic involvement clinically detectable.

Laboratory testing should include a complete blood count, an assessment of renal function, evaluation for proteinuria and haematuria, and thyroid function tests. Cryoglobulins and complement levels should be checked if there is evidence of renal disease or other compatible clinical findings. Testing for other EHM should

Mild serum amylase elevation is a common finding in HCV patients generally

The armamentarium against HCV has been expanded with the availability of molecules able to directly target non-structural proteins that play a key role in HCV replication. These agents, orally administrated for a relatively short period of time (2–3 months) have been called direct acting antivirals (DAA) and target some of the main molecular components of HCV, including NS3/4A protease (first and secondgeneration protease inhibitors), NS5B polymerase (nucleoside and non-nucleoside

DAA can cure more than 95% of persons with HCV infection, thereby reducing

Because of their not negligible rate of contraindications, important side effects,

scarce tolerability, low compliance and adherence, length course of treatment, parenteral route of administration, and the insufficient rate of sustained virological response (SVR) obtainable (not more than 60%), the interferon (IFN) based

Moreover, IFN, with its immunological stimulating properties, could be contraindicated and possibly worsen or elicit some EHM (for example thyroid disfunction, autoimmune EHM). A caution attitude could be suggested also in MC, exacerbated in some cases treated with IFN alone (without glucocorticoids). The antiviral drug ribavirin maintains a very marginal role in this context. Ribavirin common side effects are dermatologic and require caution if used in

DAA-based, IFN-free regimens should be considered the standard antiviral

At the present, DAA-based, IFN-free regimens should be used following the recommendations for individuals with HCV mono-infection in the current interna-

The vast majority of studies on the use of antiviral therapies in EHM - HCV diseases have been carried out in patients with MC vasculitis, which is considered the prototype of systemic autoimmune disease associated with HCV, both for their frequency and potential life-threatening involvement. All reported studies show that vasculitic manifestations largely improve after antiviral treatment (even in patients with partial virological responses) and often disappear, especially in

are contraindicated or not recommended during DAA therapy [22, 23].

Detailed assessment of drug–drug interactions is crucial since some medications

Treatment of low-grade lymphomas only with DAAs antiviral therapies may be recommended whereas more aggressive lymphomas would require the addition of

**13. Treatment of extrahepatic manifestations of HCV infection**

Antiviral treatment is recommended for all patients with EHM.

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

Laboratory testing should include a complete blood count, an assessment of renal function, evaluation for proteinuria and haematuria, and thyroid function tests. Cryoglobulins and complement levels should be checked if there is evidence of renal disease or other compatible clinical findings. Testing for other EHM should be guided by symptoms or specific physical findings.

Mild serum amylase elevation is a common finding in HCV patients generally without any pancreatic involvement clinically detectable.

#### **13. Treatment of extrahepatic manifestations of HCV infection**

#### **13.1 Antiviral treatment**

*Advances in Hepatology*

infection.

with HCV infection.

to the sun and/or minor trauma can lead to skin erythema and the development of

Chronic liver disease is common in sporadic PCT. Liver biopsy shows a wide range of changes, including steatosis, mild to severe inflammation, hepatic fibrosis, and cirrhosis. Environmental triggers are thought to be necessary to provoke an attack of PCT. Possible triggers of PCT include polyhalogenated hydrocarbons (such as hexachlorobenzene), oestrogens, but above all, iron overload and alcoholic beverages. The diagnosis of PCT is typically suspected on clinical grounds and is confirmed by the demonstration of markedly elevated urine uroporphyrin levels. The diagnosis can also be made directly by measuring hepatic UROD activity. All patients with PCT should be tested for HCV infection, as well as other potential disease associations, including HIV infection, iron overload, and hemochromatosis (with HFE mutation testing). Careful history of alcohol intake and testing of heavy

Management of PCT in patients with HCV infection includes avoiding precipitating factors (such as sun, alcohol, oestrogens, and polyhalogenated hydrocarbons), treating an underlying iron overload state, if present, and treating HCV

PCT often, but not always, improves with clearance of HCV viremia. The currently used pharmacological protocol for PCT include the administration of a half

Although data from individual cohorts have not been consistent, evidence overall suggests that chronic HCV infection is associated with adverse cardiovascular diseases and outcomes: dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, myocarditis, and aortic atherosclerosis. These associations are still object of debate. Because cardiovascular diseases are common and multifactorial, it is difficult to determine whether HCV is

Idiopathic pulmonary fibrosis is a serious condition described in association

Because of the associations, it is suggested testing for HCV infection in patients with clinical condition described above and other suspected to be linked to HCV. Anti-HCV antibodies (an inexpensive test) must be checked and if positive, quanti-

Conversely, patients diagnosed with chronic HCV infection should have evaluation for EHM at the initial visit and routinely during follow-up. History of an HCVinfected patient should cover rheumatologic symptoms (e.g., arthritis/arthralgias, dry eyes or mouth) and the physical exam should include a skin exam to evaluate for findings of cryoglobulinemia, PCT, and other associated dermatologic features. Superficial lymph node sites must be checked. Abdominal ultrasound is part of the HCV patient evaluation. It is in addiction necessary to perform a chest x-ray with

tative HCV-RNA, genotype and complete workup of hepatitis C performed.

Hyperpigmentation, hypopigmentation, hirsutism, and sclerodermatous

vesicles and bullae that may become haemorrhagic.

alcohol intake markers are fundamental.

tablet of chloroquine (125 mg) twice a week [19, 20].

**11. Cardiovascular and respiratory diseases**

a major contributing factor in an individual patient [3].

**12. Clinical implications and laboratory tests**

particular attention to the mediastinum.

changes may develop with the passage of time (**Figure 4**).

**38**

The armamentarium against HCV has been expanded with the availability of molecules able to directly target non-structural proteins that play a key role in HCV replication. These agents, orally administrated for a relatively short period of time (2–3 months) have been called direct acting antivirals (DAA) and target some of the main molecular components of HCV, including NS3/4A protease (first and secondgeneration protease inhibitors), NS5B polymerase (nucleoside and non-nucleoside analogues) and NS5A protein.

DAA can cure more than 95% of persons with HCV infection, thereby reducing the risk of death from cirrhosis and liver cancer.

Antiviral treatment is recommended for all patients with EHM.

Because of their not negligible rate of contraindications, important side effects, scarce tolerability, low compliance and adherence, length course of treatment, parenteral route of administration, and the insufficient rate of sustained virological response (SVR) obtainable (not more than 60%), the interferon (IFN) based therapies for HCV hepatitis must be considered obsolete.

Moreover, IFN, with its immunological stimulating properties, could be contraindicated and possibly worsen or elicit some EHM (for example thyroid disfunction, autoimmune EHM). A caution attitude could be suggested also in MC, exacerbated in some cases treated with IFN alone (without glucocorticoids).

The antiviral drug ribavirin maintains a very marginal role in this context. Ribavirin common side effects are dermatologic and require caution if used in cutaneous EHM of HCV hepatitis.

DAA-based, IFN-free regimens should be considered the standard antiviral therapeutic approach in HCV-related EHM [21].

At the present, DAA-based, IFN-free regimens should be used following the recommendations for individuals with HCV mono-infection in the current international guidelines.

Detailed assessment of drug–drug interactions is crucial since some medications are contraindicated or not recommended during DAA therapy [22, 23].

The vast majority of studies on the use of antiviral therapies in EHM - HCV diseases have been carried out in patients with MC vasculitis, which is considered the prototype of systemic autoimmune disease associated with HCV, both for their frequency and potential life-threatening involvement. All reported studies show that vasculitic manifestations largely improve after antiviral treatment (even in patients with partial virological responses) and often disappear, especially in patients with SVR.

Treatment of low-grade lymphomas only with DAAs antiviral therapies may be recommended whereas more aggressive lymphomas would require the addition of chemotherapy/rituximab.

#### *Advances in Hepatology*

IFN-free antiviral regimens might be less effective than IFN-containing regimens in some patients with B cell lymphoma, possibly due to the lack of additional anti-proliferative activity of IFN, while the association of rituximab with DAA regimens could be more effective than isolated antiviral therapies.

At the present there is little data on the response of other EHM to DAAs antiviral therapies for HCV hepatitis.

#### **13.2 Non antiviral treatment of HCV-extrahepatic manifestations**

Non-antiviral therapeutic approaches should be evaluated according to the type of EHM and the severity of the clinical presentation. The non-antiviral therapeutic approaches mainly used in EHM patients include glucocorticosteroids, immunosuppressant agents, plasma exchange and biological therapies.

Non-antiviral therapeutic approaches are recommended for moderate and, especially, for severe organ-specific involvements. Patients with moderate to severe vasculitic manifestations may be treated with short-term glucocorticoid regimens to control inflammation rapidly. Regimens of methylprednisolone (0.5–1.0 g/day) for three days followed by prednisone (not exceeding 1 mg/kg/day) may be appropriate in the setting of skin ulceration, sensorimotor neuropathy, glomerulonephritis, and other severe vasculitic manifestations.

For aggressive B cell NHL, the therapy remains based on immunochemotherapy with anthracycline-containing regimens in combination with rituximab as in HCVnegative patients.

Plasma exchange may be added to other therapies, especially in patients with severe/life-threatening cryoglobulinaemic vasculitis. Such intervention is useful in patients with immediately life-threatening involvements and for those with hyperviscosity syndrome. Apheresis techniques should always be used as a complementary therapy in combination with other strategies (antiviral therapies, B cell depleting agents).

B cell depleting agents may currently be considered to be the best biological target option for patients with the more severe EHM, always with a reasonable individualized assessment of the benefits and risks. The most promising nonantiviral therapeutic approach to HCV-related cryoglobulinemia is rituximab.

The use of antiviral therapies in combination with immunosuppressant/ biological agents should normally be made sequentially (first, use immunosuppressant/biological agents and, once the major end-organ effects have been controlled, use antiviral therapy), or concomitantly. It seems reasonable to carry out the combination on a case by-case basis [21].

The orally active thrombopoietin-receptor agonist elthrombopag may be used in severe thrombocytopenic HCV patients.

Appropriate local and systemic treatments are needed for cutaneous and ocular EHM of HCV (see above 10.) [18, 20].

#### **14. Prevention of extrahepatic manifestations treating HCV hepatitis with DAAs**

In a large population study, it was found that successful DAA treatment resulting in SVR was associated with significant reductions in the future risk of several EHM of HCV, including MC, glomerulonephritis and LP but not NHL or diabetes. The magnitude of risk reductions ranged between 0.23 and 0.61.

SVR was associated with a reduction in risk of PCT, but it was only marginally statistically significant [24].

**41**

**Author details**

Multimedica Hospital and Scientific Institute, Sesto San Giovanni, (Milano), Italy

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: albertofrosi21@gmail.com

provided the original work is properly cited.

Alberto Frosi

*Extrahepatic Manifestations of Hepatitis C Infection DOI: http://dx.doi.org/10.5772/intechopen.95995*

systemic disease rather than a disease affecting only the liver.

screening, early treatment and improved outcomes [4, 6].

sarily correlate with the severity of hepatic disease.

Chronic HCV infection can cause significant EHM and should be considered as a

EHM of HCV can affect virtually every organ via a variety of mechanisms. It is important to emphasize that the severity of these disorders does not neces-

Some investigations have shown that therapy of chronic HCV infection can result in resolution or improvement of extrahepatic diseases linked to HCV and

The author acknowledges Prof. Alberto Giannetti for the permission of

Awareness on the part of the clinician is necessary to recognize these numerous and heterogeneous pathological conditions. This in turn can lead to appropriate

**15. Conclusions**

even prevent their onset.

**Acknowledgements**

reproducing **Figure 3**.

### **15. Conclusions**

*Advances in Hepatology*

therapies for HCV hepatitis.

other severe vasculitic manifestations.

out the combination on a case by-case basis [21].

magnitude of risk reductions ranged between 0.23 and 0.61.

severe thrombocytopenic HCV patients.

EHM of HCV (see above 10.) [18, 20].

negative patients.

depleting agents).

**with DAAs**

statistically significant [24].

IFN-free antiviral regimens might be less effective than IFN-containing regimens in some patients with B cell lymphoma, possibly due to the lack of additional anti-proliferative activity of IFN, while the association of rituximab with DAA

At the present there is little data on the response of other EHM to DAAs antiviral

Non-antiviral therapeutic approaches should be evaluated according to the type of EHM and the severity of the clinical presentation. The non-antiviral therapeutic approaches mainly used in EHM patients include glucocorticosteroids, immunosup-

For aggressive B cell NHL, the therapy remains based on immunochemotherapy with anthracycline-containing regimens in combination with rituximab as in HCV-

Plasma exchange may be added to other therapies, especially in patients with severe/life-threatening cryoglobulinaemic vasculitis. Such intervention is useful in patients with immediately life-threatening involvements and for those with hyperviscosity syndrome. Apheresis techniques should always be used as a complementary therapy in combination with other strategies (antiviral therapies, B cell

B cell depleting agents may currently be considered to be the best biological target option for patients with the more severe EHM, always with a reasonable individualized assessment of the benefits and risks. The most promising nonantiviral therapeutic approach to HCV-related cryoglobulinemia is rituximab. The use of antiviral therapies in combination with immunosuppressant/ biological agents should normally be made sequentially (first, use immunosuppressant/biological agents and, once the major end-organ effects have been controlled, use antiviral therapy), or concomitantly. It seems reasonable to carry

The orally active thrombopoietin-receptor agonist elthrombopag may be used in

Appropriate local and systemic treatments are needed for cutaneous and ocular

In a large population study, it was found that successful DAA treatment resulting in SVR was associated with significant reductions in the future risk of several EHM of HCV, including MC, glomerulonephritis and LP but not NHL or diabetes. The

SVR was associated with a reduction in risk of PCT, but it was only marginally

**14. Prevention of extrahepatic manifestations treating HCV hepatitis** 

Non-antiviral therapeutic approaches are recommended for moderate and, especially, for severe organ-specific involvements. Patients with moderate to severe vasculitic manifestations may be treated with short-term glucocorticoid regimens to control inflammation rapidly. Regimens of methylprednisolone (0.5–1.0 g/day) for three days followed by prednisone (not exceeding 1 mg/kg/day) may be appropriate in the setting of skin ulceration, sensorimotor neuropathy, glomerulonephritis, and

regimens could be more effective than isolated antiviral therapies.

**13.2 Non antiviral treatment of HCV-extrahepatic manifestations**

pressant agents, plasma exchange and biological therapies.

**40**

Chronic HCV infection can cause significant EHM and should be considered as a systemic disease rather than a disease affecting only the liver.

EHM of HCV can affect virtually every organ via a variety of mechanisms.

It is important to emphasize that the severity of these disorders does not necessarily correlate with the severity of hepatic disease.

Some investigations have shown that therapy of chronic HCV infection can result in resolution or improvement of extrahepatic diseases linked to HCV and even prevent their onset.

Awareness on the part of the clinician is necessary to recognize these numerous and heterogeneous pathological conditions. This in turn can lead to appropriate screening, early treatment and improved outcomes [4, 6].

### **Acknowledgements**

The author acknowledges Prof. Alberto Giannetti for the permission of reproducing **Figure 3**.

#### **Author details**

Alberto Frosi Multimedica Hospital and Scientific Institute, Sesto San Giovanni, (Milano), Italy

\*Address all correspondence to: albertofrosi21@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

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[2] Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB. Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis 2007; 39:2-17.

[3] Negro F, Forton D, Craxì, Sulkowski MS, Feld JJ, Manns. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology 2015; 149:1345-1360.

[4] Gill K, Ghazinian H, Manch R, Gish R. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int 2016; 10:415-423.

[5] Altman N, Krzywinski M. Association, correlation and causation. Nature Methods 2015; 12: 899-900.

[6] Kuna L, Jakab J, Smolic R, Wu GY, Smolic M. HCV Extrahepatic Manifestations. Journal of Clinical and Translational Hepatology 2019;7: 172-182.

[7] Schamberg NJ, Lake-Bakaar GV. Hepatitis C Virus-related Mixed Cryoglobulinemia: Pathogenesis, Clinical Manifestations, and New Therapies. Gastroenterology and Hepatology 2007; 3: 695-703.

[8] Ferri C, Monti M, La Civita L, Longombardo G, Greco F, Pasero G, Gentilini P, Bombardieri S, Zignego AL. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 1993; 82:3701-3704.

[9] Morra E. Cryoglobulinemia. Hematology 2005;1: 368-372.

[10] Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M,

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[11] Kayali Z, Buckwold VE, Zimmerman B, Schmidt WN. Hepatitis C, cryoglobulinemia, and cirrhosis: a metaanalysis. Hepatology 2002; 36:978-985.

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[14] Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, Pasquini M, Marchi S, Ferrannini E. Thyroid disorders in chronic hepatitis C. Am J Med 2004;117:10-13.

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[16] Martin P, Fabrizi F. Hepatitis C virus and kidney disease. Journal of Hepatology 2008; 49: 613-624.

[17] Mignogna MD, Lo Muzio L, Lo Russo L, Fedele S, Ruoppo E, Bucci E. Oral lichen planus: different clinical features in HCV-positive and HCVnegative patients. Int J Dermatol 2000; 39:134-139.

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**43**

49:1442-1447.

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[19] Gisbert JP, García-Buey L,

of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepat 2003;

[20] Biolcati G. Porphyrias. In: Giannetti A, Del Forno C, editors. Textbook of Dermatology and Sexual Transmitted Diseases. Piccin; 2013.

[21] Ramos-Casals M, Zignego AL , Ferri C, Brito-Zerón P,

J Hepat 2017; 66:1282-1299.

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[23] European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol 2020;73: 1170-1218.

[24] El-Serag HB, Christie IC, Puenpatom A, Castillo D, Kanwal F, Kramer JR. The effects of directly acting antiviral-related sustained virological response on the risk of extrahepatic manifestations of hepatitis C infection.

Aliment Pharmacol Ther 2019;

Retamozo S, Casato M, Lamprecht P, Mangia A, Saadoun D, Tzioufas AG, Younossi ZM, Cacoub P, on behalf of the International Study Group of Extrahepatic Manifestations related to HCV (ISG-EHCV). Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection.

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Giannetti A, Del Forno C, editors. Textbook of Dermatology and Sexual Transmitted Diseases. Piccin; 2013. p. 1225-1244.

[19] Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepat 2003; 39: 620-627.

[20] Biolcati G. Porphyrias. In: Giannetti A, Del Forno C, editors. Textbook of Dermatology and Sexual Transmitted Diseases. Piccin; 2013. p. 2021-2044.

[21] Ramos-Casals M, Zignego AL , Ferri C, Brito-Zerón P, Retamozo S, Casato M, Lamprecht P, Mangia A, Saadoun D, Tzioufas AG, Younossi ZM, Cacoub P, on behalf of the International Study Group of Extrahepatic Manifestations related to HCV (ISG-EHCV). Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection. J Hepat 2017; 66:1282-1299.

[22] AASLD-IDSA Hepatitis C Guidance Panel. Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Hepatology 2020;71: 686-721.

[23] European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol 2020;73: 1170-1218.

[24] El-Serag HB, Christie IC, Puenpatom A, Castillo D, Kanwal F, Kramer JR. The effects of directly acting antiviral-related sustained virological response on the risk of extrahepatic manifestations of hepatitis C infection. Aliment Pharmacol Ther 2019; 49:1442-1447.

**42**

*Advances in Hepatology*

**References**

[1] Spearman CW, Dusheiko GM, Hellard M, Sonderup M. Hepatitis C. Grippon P, Hoang C, Piette JC,

in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994; 106:1291-1300.

[11] Kayali Z, Buckwold VE,

[12] Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, Engels EA. Risk of non-Hodgkin lymphoma and

JAMA 2007; 297:2010-2017.

Hureaux JM, Opolon. Cryoglobulinemia

Zimmerman B, Schmidt WN. Hepatitis C, cryoglobulinemia, and cirrhosis: a metaanalysis. Hepatology 2002; 36:978-985.

lymphoproliferative precursor diseases in US veterans with hepatitis C virus.

[13] Pioltelli P , Gargantini L, Cassi E, Santoleri E, Bellati G, Magliano EM, Morra E. Hepatitis C virus in non-Hodgkin's lymphoma. A reappraisal after a prospective case-control study of 300 patients. Lombard Study Group of HCV-Lymphoma (Frosi A. and others).

Am J Hematol 2000; 64:95-100.

2004;117:10-13.

39:134-139.

[14] Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, Pasquini M, Marchi S, Ferrannini E. Thyroid disorders in chronic hepatitis C. Am J Med

[15] White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and metaanalysis. J Hepatol 2008; 49:831-844.

[16] Martin P, Fabrizi F. Hepatitis C virus and kidney disease. Journal of Hepatology 2008; 49: 613-624.

[17] Mignogna MD, Lo Muzio L, Lo Russo L, Fedele S, Ruoppo E, Bucci E. Oral lichen planus: different clinical features in HCV-positive and HCVnegative patients. Int J Dermatol 2000;

[18] Cottoni F, Montesu MA. Lichen Planus, Lichen Nitidus. In:

[2] Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB. Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. Dig

Lancet 2019; 394:1451-1466.

Liver Dis 2007; 39:2-17.

2015; 149:1345-1360.

[3] Negro F, Forton D, Craxì, Sulkowski MS, Feld JJ, Manns.

Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology

[4] Gill K, Ghazinian H, Manch R, Gish R. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int 2016; 10:415-423.

[5] Altman N, Krzywinski M.

[6] Kuna L, Jakab J, Smolic R,

172-182.

Association, correlation and causation. Nature Methods 2015; 12: 899-900.

Wu GY, Smolic M. HCV Extrahepatic Manifestations. Journal of Clinical and Translational Hepatology 2019;7:

[7] Schamberg NJ, Lake-Bakaar GV. Hepatitis C Virus-related Mixed Cryoglobulinemia: Pathogenesis, Clinical Manifestations, and New Therapies. Gastroenterology and Hepatology 2007; 3: 695-703.

Civita L, Longombardo G, Greco F, Pasero G, Gentilini P, Bombardieri S, Zignego AL. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood

[9] Morra E. Cryoglobulinemia. Hematology 2005;1: 368-372.

[10] Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M,

[8] Ferri C, Monti M, La

1993; 82:3701-3704.

**45**

Section 4

Antiviral Treatments

Section 4
