Hepatitis

➢ Introduction

Viral Hepatitis, a worldwide disease, is an Inflammation in the liver may be caused by a variety
of viruses, by which the liver is not the main affected organ , including Epstein-Barr virus,
Herpes virus and Cytomegalovirus. The most specific and accused family is Hepatotropic
viruses, divided into groups A to E. In the same group may possess another division into
genotypes. Some groups are notable in specific regions around the world. World Health
Organization WHO declared in 2015 that there are approximately 380 Million Viral Hepatitis
globally, causing an estimated 1,5 Million deaths. These viruses are likely to be found in
developing countries with low hygienic techniques. Therefore, scientists tried among the last 4
decades to overcome this struggle and give out treatment and vaccination to this life threatening
disease

These viruses are more spreaded in developing countries with low sanitation like Western
pacific, African and southeast Asia (WHO 2015) .

Among the Hepadnavirus family the most important are Hepatitis B Virus HBV and Hepatitis C
Virus, the 2 viruses resulting in 1.2 M deaths annually.

A,D and E are mostly transmitted by the faeco-oral way , either eating contaminated food or
water, For HBV and HCV the transmission could occur through donating blood or plasma
(donators need screening before proceeding ), contaminated needles, metals and tattooing stuffs (
abusers using same syringe, renal dialysis and those who need frequently blood e.g.
Hemophiliacs ). HBsAg may appear in semen, vaginal secretions and saliva ( homosexual or
unprotected intercourse =horizontal transmission ). Also during delivery if the mother is infected
(vertical transmission) (could cause the infant to develop chronic HBV ) .

Patients maybe symptomatic or asymptomatic : according to host immunity and severity of

infection or genetic malfunctions.
Some of the symptoms patients may report: Anorexia, hepatomegaly, fever, jaundice and dark
urine.

HBV and HCV are known to be the main risk factors for HCC [1].

➢ Brief virology info : HBV consists of Dane particles (called virions) ’42 nm ‘ divided
into outer lipid layer and the core is icosahedral nucleocapsid , and HB surface Antigen
(HBsAg). The nucleocapasid consists of HB core antigen(HBcAg) attached to the viral
DNA genome Which is partially double stranded circular DNA dsDNA , HBV is
enveloped possessing HB envelope Antigen (HBeAg). There are 10 HBV DNA
genotypes (A -J) , spreaded worldwide in low income countries, genotypes B and C are
mostly located in eastern and southeastern Asia, the rest in Africa, Europe and North
America. Genotype C is most virulent, many studies declared that patients with HBV
Type C are more likely to be associated with advanced fibrosis, cirrhosis and liver
cancer[2].

Developing of Hepatitis is due to the host immune response, let’s figure out how does that
happen

➢ Pathogenesis

Either any of the hepatitis viruses, it has to reach the liver (Hepatocytes), no matter through
enteric or bloodstream pathway, and does its replication cycle ( DNA or RNA ) in Hepatocytes
where it binds to sodium taurocholate co-transporting polypeptide (NTCP) receptor on
Hepatocytes surface using pre-s1 domain of HBsAg, the virus itself is non cytopathic the
pathogenicity refers to the host immune response, both Humoral and Cellular immunity
cooperates with each other to eliminate the virus. First, the Cytotoxic T Lymphocytes specific
CD8 [CTLs] recognize the HBsAg (due to over expression of Long-HBsAg on
Hepatocytes)leading to initiation of apoptosis of Hepatocytes through activation of Fas ligand
(FasL) and perforin which death of these cells depends on. Second, increase up levels of
Interferon gamma (INF-γ) and Tumor Necrosis Factor alpha (TNF-α). Latter two factors help in
cell apoptosis, killing virus(inhibition of expression of HBV) and recruiting more non specific
inflammatory cells, Resulting at the end to the elimination of virus k and regeneration of the
Hepatocytes. All these process occur in the Acute hepatitis, But for the Chronic Hepatitis there
are : Persistent inflammation leading to fibrosis, cirrhosis and maybe Hepatocellular Carcinoma
(HCC)(duke to repeated cell death and regeneration and mutation )[3]. ALSO, it was found that
NkG2D and 2B4 levels (activating receptors of Natural Killer cells )were reduced which
thereby impair the function of NK (which helps in innate immunity). Furthermore, HBsAg cause
CTLs to exhaust.

• Figure.2. HBV cycle of life and proper mechanisms for treatment. [5]

➢ Laboratory Diagnosis

For most Hepatitis viruses detection of increased levels of enzymes of the liver and bilirubin
may be an easy way but not a confirmatory one.

In case of HBV, best way is to detect Antigens and Antibodies (markers).

Using ELISA.

In Acute HBV : Primarily, HBsAg and HBeAg are the first to show up( first 1-2 weeks) HBeAg
vanishes so quickly one week later then HBsAg follows it ( if HBsAg persist for longer duration
that indicates chronicity ), Alanine and Aspartate Aminotransferase (ALT and AST)begin to rise
in serum which may be associated with jaundice, HBcAg doesn’t appear in serum, it’s found in
the hepatocyte nuclei.

Secondly, Host immunity responds to these Antigens and produce Antibodies, the first to rise
Anti-HBc (mainly Immunoglobulin M IgM) then begins to disappear in serum while IgG Anti
HBc appears in serum, Anti HBeAg levels grow after vanishing of HBeAg ( considered a
beneficial mark) indicating that recovery stage begun. Lately, at week six, Anti HBs rise up and
becomes the defense mark against future infection. Nevertheless, Anti HBc detection is most
dependable to check previous infection( as 10-15% of patients don’t give out Anti HBs).
Figure 3 and 4. Explanation of serum markers and host Anti bodies. For both chronic and
Acute. [6]

For HBV DNA it is suggested by worldwide guidelines to start antiviral therapy if levels of ALT
and HBV DNA we above 20,000 IU/ml, or if patient with cirrhosis and found HBV DNA in
serum (which may refer to virus existence).[7]. HBV DNA is very beneficial to assess anti viral
therapy (will be discussed later ). Also for Chronic Hepatitis B (CHB) most noticeable markers
are HBsAg, HBeAg and HBV DNA . Although HBV DNA may be not found in serum by time
but HBeAg and HBsAg levels remain.

Moreover, we can use many methods to detect HBV genotyping (which may predict the stage of
progression) like reverse hybridization, genotype-specific PCR, real time PCR, restriction
fragment-length polymorphism and more.

➢ Goals of Prophylaxis and Vaccination : -production of T cells (specific for virus

)- Activation of viral immunity specific cells (e.g., T cells ,B cells and dendritic cells )-
improve T cell function so not to exhaust in case of chronicity.

Immune prophylaxis : Recombivax ( a recombinant vaccine made in yeast )used in Egypt to

infants at 2,4,6 months.

For HBV positive mothers, to prevent vertical transmission, using Hepatitis B specific
Immunoglobulin (HBIG) and vaccine is a good choice.

➢ Treatment

Pharmacological excitation of host innate immunity and increasing the activity of HBV-specific
T and B cells [8]

Toll-like receptor 7 (TLR7): Vesatolimod (oral )which acts as agonist on TLR7, it has reduced
perfectly levels of HBV DNA , HBsAg and rates of HCC development.
TLR8 is far different from TLR7, it’s functioning on suppressing the evolvement of professional
antigen cells. Furthermore, increasing efficiency of Anti -HBV (TCLs specific). Prototype of
this family ( GS-9688) it’s still not approved yet. [9]

Studies recently showed that mycrludex B (derived from L-HBsAg )can suppress NTCP
(irreversible blocking ).(target is HBV cycle of life ) [10].

CpAMs (e.g.,. GLS4)act through different mechanisms :

- Hindrance of assembly of HBcAg (inhibiting replication )

- Reduction of cccDNA synthesis

- Stimulation of Interferon -stimulated gene (ISG)expression [11]

The combination of CpAMs with nucleos(t)ide drugs NUCs proved huge success in inhibition of
replication and formation of de novo of cccDNA. [12].

HBx (or core protein) considered to involve in cccDNA transcription.

There are two promising drugs meant to inhibit this pathway:

1- Pevonedistat, an in vitro study on hepatocytes in culture declared that

Pevonedistat(inhibitor to NEDD8-activating enzyme) was able to restore SMC5/6 and
inhibiting viral transcription and RAN translation.
2- Nitazoxanide, approved by Food and Drug Administration (FDA)for Protozoan enteritis,
like pevonedistat except for inhibition of NEDD8-activating enzyme and plus successful
inhibition of interaction of HBx with DDB1 ( DNA damage-binding protein1 DDB1 is
transported by HBx to SMC5/6 for degradation) = inhibition of transcription of cccDNA.
[13], [14]

Sofosbuvir (SOF) is a nucleotide analog polymerase inhibitor of Nonstructural

protein (NS-5B) and it is the most essential DAA used in combination with drugs
for the treatment of HCV infection. The fixed-dose combination of sofosbuvir
(SOF) and ledipasVir (LED) is approved for the treatment of chronic HCV
infection Worldwide. LED/SOF combination exhibits a favorable drug-drug
Interaction profile and can be administered with various medications that may be
used by HCV-infected patients, including patients with comorbidities, such as co-
infection with human Immunodeficiency virus or immunosuppression following
liver transplantation. Other important HCV antiviral drugs commonly Co-
administered with SOF include daclatasvir (DAC) and Ribavirin. [17]

➢ Summary

Now it’s obvious how dangerous and fatal Hepatitis viruses are. They just doing
nothing, all blames are towards the host immunity.

Most of the drugs mentioned above are still under trials and they work on the virus
itself whether on cccDNA replication, virus entry, binding sites or preventing
transcription. Few work to stimulate immunity which is the most important target.
May vaccines be the winning card to overcome this problem. People always need
to analyze their body and follow up with physicians to check if there is infection or
not ( could be a carrier without symptoms).

Further investigations need to focus more on creating more affordable vaccines and
antiviral drugs. The Researches won’t stop till we control the disease and the
infection.
References

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