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Hepatitis B – Epidemiology, Symptoms, Causes, Pathophysiology, Risk Factors, Diagnostic Measures, & Treatments

Dr. Khalid is a physician, a researcher, a health writer, and holds a Ph.D. in clinical research.

Hepatitis B: A Comprehensive Evidence-Based Analysis

What is Hepatitis B?

The small DNA virus (i.e. hepatitis B virus [HBV]) is a member of the Hepadnaviridae family and exhibits the attributes and structure of retroviruses (Liang, 2009). The eight genotypes of HBV are associated with a unique geographical pattern. The electron microscopy helps in evaluating the structure of these virus particles in the serum of the infected patients. HBV impacts greater than 300 million individuals across the globe. Most importantly HBV proves to be the biggest cause of life-threatening conditions including liver cancer and liver disease. The RNA intermediate of HBV facilitates its integration into the genome of the infected host. The consistent replication of HBV into the host cell lines helps its long-term sustenance within the host body. The serological assays and virological analysis support the timely identification of chronic hepatitis B and HBV-associated disease. The HBV infection leads to the development of a range of critical/debilitating conditions including hepatocellular carcinoma, cirrhosis, chronic hepatitis and acute liver failure (Liang, 2009).

The development of acute HBV infection is followed by the development of acute hepatitis and its clinical symptoms. However, many patients develop HBV infection in the absence of symptoms or clinical complications. 5% to 10% of individuals exposed to HBV fail to recover and develop chronic infection. Some of the chronically infected hepatitis B patients exhibit mild liver complications; however, many of them actively develop disease manifestations leading to liver carcinoma and cirrhosis. The thorough assessment of such patients is highly warranted for the customization of pharmacotherapy and person-centered health care interventions. Hepatitis B patients rarely develop extrahepatic manifestations (Liang, 2009). The physicians encounter several challenges in managing/diagnosing HBV manifestations and accomplishing the unmet patient demands. The prediction of HBV prognosis also appears difficult in the absence of disease knowledge and clinical skills. Prospective research studies are highly warranted in the context of evaluating the genetic, immunological, cellular, and molecular basis of HBV in infected patients.

Epidemiology of Hepatitis B

HBV impacts populations of various age groups across geographically diverse regions of the globe (MacLachlan & Cowie, 2015). Liver manifestations, blood-borne viruses, and other coinfections potentially elevate the overall burden of HBV and its infectious outcomes. HBV infection is the leading cause of morbidity on a global scale. The order of HBV prevalence reciprocates with the virus exposure level and quality of treatment interventions.

Populations with Elevated HBV Prevalence

Hepatitis B infection potentially impacts the health, wellness, and quality of life of the 45% population of the world. Sub-Saharan African and Asian Pacific regions experience a high burden of HBV due to vertical transmission (MacLachlan & Cowie, 2015). HBV in these locations predominantly infects young females of childbearing age. The detection of HBV infection in such females occurs through the tracking of HBV DNA and HBeAg (hepatitis B e-antigen). HBV infects 8% of individuals across the high-risk regions of the globe. The universal infant vaccination proves to be the feasible measure to reduce the production of HbsAg (hepatitis B surface antigen) in the infected children.

Populations with Intermediate HBV Prevalence

2%-7% of the world’s populations across the globe encounter HBV exposure across immediate prevalence regions of South Asia, Latin America, Southern Europe, Eastern Europe, Middle East and North Africa (MacLachlan & Cowie, 2015). These regions of the globe exhibit horizontal or perinatal transmission of the hepatitis B virus.

Populations with Reduced HBV Prevalence

12% of the population across the globe experience or acquire HBV infection across South America, Japan, Western Europe, Northern Europe, Asia, and Australia (MacLachlan & Cowie, 2015). These regions associate a limited risk of horizontal and vertical transmissions. However, the infected individuals acquire the disease based on their blood-related exposure, utilization of injectable drugs, and venereal contact. Such infected populations comprise of adults and adolescents in particular. 0.3-2.7 million people across the globe live with HBV status based on their exposure to injectable drugs. Furthermore, homeless people, LGBT community members, and incarcerated individuals experience an elevated risk of contracting HBV infection and associated comorbidities. Australia antigen or HBsAg majorly impacts Indigenous Taiwanese, Maori, and Aboriginal people in circumpolar territories, Arctic regions, Native North American locations, and Amazon regions. These populations frequently contact HBV infection due to multifactorial causes. Some of the potential contributors to HBV infection in tribal people include the following.

  1. Inaccessible primary health care services
  2. Lack of health education
  3. Inappropriate primary health care services
  4. The blood-to-blood exposure
  5. The elevated residual density of HBV
  6. Elevated maternal viral load
  7. Early pregnancy
Hepatitis B Surface Antigen Prevalence

Hepatitis B Surface Antigen Prevalence

What are the Symptoms of Hepatitis B?

Most of the hepatitis B patients do not encounter clinical symptoms, particularly during their initial phase of HBV exposure (World Health Organization, 2019). However, some of the acute manifestations experienced by infected patients include the following.

  1. Jaundice, manifested by yellowing of eyes and skin
  2. Extreme debility or fatigue
  3. Dark-colored urine
  4. Abdominal pain
  5. Vomiting
  6. Nausea

Liver failure proves to the greatest cause of death among HBV infected patients. The development of chronic liver infection in hepatitis B patients is followed by liver scarring or cirrhosis that in some scenarios transforms into hepatic/liver cancer or hepatocellular carcinoma.

What are the Risk Factors of Hepatitis B?

The predisposition of individuals towards HBV infection reciprocates with their age groups. For example, the children experience an increased risk of chronic infection following their exposure to the hepatitis B virus (World Health Organization, 2019). More than 80% of infants who experience HBV infection during the initial year of their life acquire chronic infection. Similarly, children below 6 years of age exhibit an elevated tendency to develop a chronic infection following their initial exposure to the hepatitis B virus.

Adults rarely acquire chronic infection following their initial exposure to the hepatitis B virus. 20%-30% of the 5% of adults who become the victim of chronic infections develop liver cancer and/or cirrhosis.

What are the Causes of HBV Transmission?

  1. Perinatal transmission prevalently occurs across highly endemic locations. This indicates that the children acquire the disease from their mothers and eventually develop clinical complications (World Health Organization, 2019). Furthermore, horizontal transmission occurs when healthy individuals contact the infected blood and develop HBV manifestations. For example, a healthy child could develop the disease after contacting an HBV infected child until five years of age. The infants prevalently develop a chronic infection following the HBV exposure from their mothers.
  2. Needle-stick injury due to piercing and/or tattooing activities also elevates the occurrence of HBV infection in the affected people (World Health Organization, 2019). Furthermore, exposure to seminal/vaginal/menstrual fluids, saliva, and infected blood also predispose the individuals towards the development of HBV infection. Unvaccinated men engaged in unsafe venereal practices exhibit a high tendency to acquire HBV infection.
  3. The re-utilization of syringes and needles in the hospital settings also increases the risk of contracting hepatitis B infection, particularly in adults (World Health Organization, 2019).
  4. Some other noticeable sources of HBV infection include contaminated razors, tattooing procedures, dental procedures, and surgical interventions (World Health Organization, 2019).
  5. HBV could sustain for a duration of seven days outside the human host. However, HBV outside the human host possesses the ability to cause infections to healthy individuals (World Health Organization, 2019). HBV incubation period ranges from 75-180 days. However, in some cases, infected patients develop symptoms or clinical manifestations within 30 days of initial exposure. Most importantly, the survival of HBV inside the human host for a duration of 30-60 days greatly increases the risk for chronic hepatitis B.

What is the Pathophysiology of Hepatitis B?

The severity of HBV varies considerably from one individual to another based on its ability to cause necroinflammation liver disease. Hepatocellular carcinoma and cirrhosis emanate through the long-term survival and sustenance of HBV inside the human host. HBV infects hepatocytes in many clinical scenarios without producing any biochemical evidence of hepatic complications. HBV rapidly replicates in immunocompromised individuals. Accordingly, pharmacological suppression of cellular immune responses potentially elevates the risk of HBV infection in treated patients. The adaptive immune responses of the hepatitis B patients mediate their disease pathogenesis and viral clearance. HBV manages to evade or suppress the immune responses of the infected patients for expanding its survival through uninterrupted replication. HBV infection drastically reduces the potential of T cells in a manner that they fail to counteract the viral load. The chronic liver infection in HBV patients reciprocates through the hypo-responsiveness of CD8+ T cells. The early CD4+ T cell priming governs the CD8+ T cell responses in HBV patients. The intensity of these responses reciprocates with the magnitude of viral inoculum. The T cell-derived cytokines govern the HBV (noncytopathic) clearance from the infected host. The CD8+CTL complex effectively recognizes the antigenic invasion and induces apoptosis in the context of destroying the intruder cells. Furthermore, the generation of cytokines including TNF-α and IFNγ assists in challenging viral gene expression, sustenance, and replication.

Hepatitis B Antigen Recognition

Hepatitis B Antigen Recognition

HBV Life Cycle

HBV Life Cycle

What are the Diagnostic Measures for Hepatitis B Detection?

A thorough understanding of HBV structure is highly needed before undertaking its microscopic analysis (Song & Kim, 2016). The structure of the HBV virus is based on the icosahedral capsid protein core, HBsAg (Hepatitis B surface antigen), and is lipid envelope. The overall diameter of HBV ranges between 30-42nm. The DNA polymerase and viral genome are the preliminary components of the hepatitis B viral capsid. The partly double-stranded DNA of the HBV genome exhibits reverse transcriptase activity and incorporates 4-open reading frames embedded on each other (Song & Kim, 2016). Some of the significant diagnostic interventions for HBV detection include the following.

Serological Analysis

The serological assessment helps in evaluating the diagnostic markers including IgG, anti-HBc IgM, anti-HBe, HBeAg, anti-HBs, and HBsAg (Song & Kim, 2016). The serological marker evaluation helps in achieving the following diagnostic goals.

  1. Evaluation of the natural course of chronic hepatitis B and its clinical manifestations
  2. Evaluation of HBV infection’s clinical phases
  3. Evaluation of antiviral therapy

Molecular Methods

The molecular approaches help in evaluating the HBV’s replication activity and overall viral load (Song & Kim, 2016). The molecular methods provide the advantage of an early HBV detection (i.e. within the timeframe of 3-month) following initial virus exposure. Some of the frequently utilized molecular methods include the following.

  1. Branched DNA analysis
  2. Automated real-time PCR (i.e. target amplification)
  3. Semi-automated real-time PCR (i.e. target amplification)
  4. Semi-automated qPCR (i.e. target amplification)

The above-listed diagnostic methods help in detecting HBV DNA during the early stage of disease progression (Song & Kim, 2016). These tests efficiently detect serologically negative HBV cases. HBV DNA assessment proves to be a robust measure for evaluating the requirement of antiviral therapy or other similar meaningful treatments. PCR amplification technique helps in assessing the viral load in a variety of HBV suspected cases.

HBV Genotyping

The elevated genetic heterogeneity of HBV substantiates the utilization of HBV genotyping for tracking its replication through reverse transcriptase activity inside the host body (Song & Kim, 2016). HBV genotyping not only helps in tracking the onset and progression of HBV but also assists physicians to configure the appropriate person-centered antiviral treatments. HBV genotyping helps in diagnosing HBV genotypes A, B, C, and D. The assessment of genotype C helps in evaluating the occurrence of hepatocellular carcinoma (HCC), severe liver disease, and perinatal infection. However, the tracking of genotypes D and A helps in evaluating the progression of chronic HBV infection (Song & Kim, 2016). The clinical studies have affirmed greater treatment outcomes for the patients affected with HBV genotypes D and C. Contrarily, tenofovir pharmacotherapy does not potentially challenge the development of genotypes C and B. These evidence-based outcomes reveal the role of HBV genotyping in deciding the appropriate therapeutic interventions for HBV infected patients (Song & Kim, 2016). HBV genotyping is categorized into the following subtypes.

  1. Sequence Analysis
  2. Genotype-specific polymerase chain reaction (PCR)
  3. Reverse hybridization
  4. Restriction fragment length polymorphism (RFLP)

Other Commonly used Hepatitis B Infection Detection Methods

Elevated serum aminotransferases, clinical symptoms, and HBsAg detection lead to the diagnosis of acute hepatitis B (Song & Kim, 2016). The acute phase of HBV infection manifests through the elevation in HBeAg, HBV DNA, and anti-HBC IgM. The consistent detection of HbsAg for a duration for 24 weeks or more affirms the occurrence of hepatitis B infection in the suspected individuals. The clinical presentations fail to affirm the diagnosis of chronic HBV in the absence of a laboratory examination. The previous history of HBV infection is marked by the concomitant presence of IgG anti-HBc and anti-HBs (Song & Kim, 2016). The absence of HBsAg and reduced percentage of intrahepatic HBV DNA inside the host body mark the presence of occult HBV infection. The mode of transmission of occult hepatitis B virus infection includes orthotopic/solid organ liver transplantation and transfusion. Furthermore, immunocompromised patients or patients receiving chemotherapy experience an elevated risk of HBV infection (Song & Kim, 2016). The occult hepatitis B infection is marked by the absence of hepatitis B surface antigen and elevated level of serum HBV DNA (Hou, Liu, & Gu, 2005). The patients affected with chronic hepatitis C infection/chronic liver disease experience a hepatic injury following their exposure to the hepatitis B virus. Eventually, such patients experience hepatic fibrosis and inflammation that potentially elevate their predisposition for hepatocellular carcinoma. The occult HBV infection also develops under the influence of the following conditions (Song & Kim, 2016).

  1. Cryptogenic liver disease
  2. Presence of serum anti-HBC
  3. Chemotherapy
  4. Immunosuppression therapy
  5. Donors in solid organ transplants

What is the Standard Treatment for Hepatitis B?

The following antiviral drugs have been approved by the US FDA (Food and Drug Administration) for the systematic treatment of chronic hepatitis B virus infection (Rajbhandari & Chung, 2016).

  1. Interferon-a2b
  2. Peg-IFN (pegylated interferon a2α) [first-line agent]
  3. LAM (Lamivudine)
  4. Adefovir
  5. ETV (entecavir) [first-line agent]
  6. Telbivudine
  7. TDF (tenofovir) [first-line agent]

The combination treatment with ETV/TDF and Peg-IFN is recommended for immune active cases marked by the presence of HBV DNA (greater than 20,000 IU per ml), ALT (alanine aminotransferase)>2, and hepatitis B e antigen+ (Rajbhandari & Chung, 2016). The treatment lasts for a duration of 48-52 weeks. The therapeutic administration of interferon-a2b is warranted until the complete disappearance of HBV DNA and HBeAg (hepatitis B e-antigen) seroconversion. Furthermore, the detection of anti-HBe warrants the administration of 6-monthly treatment to reduce the risk of disease relapse. However, lifelong therapy with ETV or TDF is highly recommended for the treatment of compensated/decompensated cirrhosis. The physicians recommend ETV administration for the systematic treatment of fulminant hepatitis B or symptomatic/acute hepatitis B (Rajbhandari & Chung, 2016). The lifelong treatment with ETV is recommended for liver transplant patients or in other patients until their complete clearance of HBeAg. Since HBV carriers experience an elevated risk of HBV reactivation, ETV or TDF therapy is recommended before the administration of immunosuppressive treatment or chemotherapy. The physicians recommend the accomplishment of treatment endpoints in patients who exhibit a baseline DNA level of greater than 2,000 units per ml (Rajbhandari & Chung, 2016). However, 6-monthly ETV or TDF administration is recommended for the patients who exhibit a reduced level of HBV DNA (i.e. less than 2, 000 units per ml). The elevated HBV load of pregnant mothers with 28-30 weeks gestation requires treatment with LAM or TDF. However, the consistent clinical monitoring of these pregnant mothers is highly recommended after their therapy cessation and/or delivery to reduce the risk of HBV flares. HBV patients who develop HIV infection require lifelong treatment with LAM/emtricitabine and TDF (Rajbhandari & Chung, 2016). Alternatively, the administration of consolidation treatment based on and antiretroviral regimen with ETV is also recommended until the acquisition of HBeAg seroconversion.

What is the Prevention of Hepatitis B Infection? (Hepatitis B Prevention Tips)

Immunization

HBV vaccination (active immunization) or HBIG vaccination (passive immunization) are highly recommended to effectively control the incidence and prevalence of hepatitis B virus infection on a global scale (Chang & Chen, 2015). The administration of yeast recombinant hepatitis B vaccine (5-microgram dosage) to infants potentially reduces their risk of acquiring chronic hepatitis B infection. Furthermore, the utilization of the plasma-derived hepatitis B vaccine extends a protective effect to the high-risk people while providing them 90% safety from HBV manifestations. Passive immunization is recommended for high-risk patients in the following scenarios (Hou, Liu, & Gu, 2005).

  1. Liver transplantation
  2. Venereal exposure
  3. Needlestick exposure
  4. HBV infection in mother of new-borns

Active immunization against HBV helps in reducing the risk of primary infection. Routine immunization of infants is highly recommended within a day of their birth to minimize their predisposition towards chronic hepatitis B virus infection (World Health Organization, 2019). The three-dose schedule of hepatitis B vaccine to infants begins with the administration of initial dose on the date of birth followed by subsequent (2nd and 3rd) dosages that warrant administration with 1st and 3rd dosages of DTP (diphtheria-pertussis-tetanus) vaccine. Similarly, the four-dose schedule is based on the administration of combination dosages (after 1st dose at birth) with other immunization procedures. Most importantly, the adolescents who never received the hepatitis B vaccine and reside in intermediate or low endemicity locations require immunization on priority to reduce their risk for HBV infection. Hepatitis B vaccination is also recommended for the below-mentioned individuals following the WHO guidelines (World Health Organization, 2019).

  1. Individuals engaged with unsafe venereal practices or multiple intimate partners
  2. Individuals in physical/household contact with HBV infected patients
  3. Individuals in contact with blood products and/or blood
  4. Unvaccinated travelers
  5. Individuals who receive injectables
  6. Prisoners
  7. Patients requiring solid organ transplantations, dialysis, and infusion of blood products/blood

Policy Recommendations

The WHO recommends the implementation of the following measures to minimize the global prevalence of hepatitis B infection (World Health Organization, 2019).

  1. The 1st and 2nd line pharmacotherapy must include entecavir or entecavir plus tenofovir (i.e. the analogs with a limited scope of drug resistance by the invading virus) for treating children within the age group of 2-11 years
  2. The treatment priority should reciprocate with the infected patients’ mortality risk and liver disease level
  3. The patients affected with advanced liver disease must receive immediate treatment after their diagnostic assessment
  4. Treatment accessibility and liver disease stage assessments warrant the utilization of non-invasive diagnostic interventions in hospital settings.
  5. The scaling of treatment services, person-centered health care, and screening is highly warranted to effectively check the progression of HBV infection
  6. The prevention of HBV transmission is highly warranted through high compliance with hygiene measures and healthy behaviors
  7. The formulation of action data and evidence-based policy is essentially required to improve the quality of HBV prevention and treatment inside the health care setting

The mobilization of resources, health care partnership promotions and awareness interventions include some of the robust measures requiring implementation to reduce the prevalence of hepatitis B virus infection and associated comorbidities.

What is the Alternative/Natural/Herbal Treatment of Hepatitis B?

Unani System of Medicine offers robust remedies for the prevention and treatment of hepatitis B infection. Some of the potential oral formulations are listed below (Fasihuzzaman, Mushtaq, & Ansari, 2015).

1. Arq Makoh (Dosage: 50ml both times a day)

2. Majoon Dabidul Warad (Dosage: 10grams both times a day)

3. Sharbat Bazoori (Dosage: 25ml both times a day)

4. Jawarish Pudina Walaiti (Dosage: 10grams evening)

5. Jawarish Anarain (Dosage: 10grams following the consumption of meals)

6. Hab-e-Kabid Naushadri (Dosage: 1 tablet three times a day)

7. Capsule Jigreena (Dosage: 2-capsules both times a day)

8. Sharbat Jigreen (Dosage: 20ml both times a day)

Unani therapy requires administration for a minimum duration of four months for achieving therapeutic goals. The detoxifying and hepatoprotective effects of the above-mentioned formulation help in reducing the risk of HBV infection in predisposed patients. However, the concomitant administration of these standalone Herbal/Unani formations is not recommended with standard pharmacotherapy. Prospective research studies are necessarily required to enhance the quality and efficacy of HBV prevention and treatment interventions. The patients must consult with qualified physicians and health care experts to formulate holistic and person-centered treatment regimens for treating their HBV infection.

References

Chang, M. H., & Chen, D. S. (2015). Prevention of Hepatitis B. Cold Spring Harb Perspect Med, 1-12. doi:10.1101/cshperspect.a021493

Fasihuzzaman, Mushtaq, S., & Ansari, S. (2015). Chronic hepatitis B treated with oral unani medication along with fasd (venesection). International Journal of Advances in Pharmacy, Medicine, and Bioallied Sciences. Retrieved from http://biomedjournal.com/chronic-hepatitis-b-treated-with-oral-unani-medication-along-with-fasd-venesection-2/

Hou, J., Liu, Z., & Gu, F. (2005). Epidemiology and Prevention of Hepatitis B Virus Infection. International Journal of Medical Sciences, 2(1), 50-57. doi:10.7150/ijms.2.50

Liang, T. J. (2009). Hepatitis B: The Virus and Disease. Hepatology, 49(5), S13–S21. doi:10.1002/hep.22881

MacLachlan, J. H., & Cowie, B. C. (2015). Hepatitis B Virus Epidemiology. Cold Spring Harbor Perspectives in Medicicne. doi:10.1101/cshperspect.a021410

Rajbhandari, R., & Chung, R. T. (2016). Treatment of Hepatitis B: A Concise Review. Clinical and Translational Gastroenterology, 7(9), 1-10. doi:10.1038/ctg.2016.46

Song, J. E., & Kim, D. Y. (2016). Diagnosis of hepatitis B. Annals of Translational Medicine, 4(18), 1-6. doi:10.21037/atm.2016.09.11

World_Health_Organization. (2019, 07 18). Hepatitis B. Retrieved from https://www.who.int/news-room/fact-sheets/detail/hepatitis-b

This content is for informational purposes only and does not substitute for formal and individualized diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed medical professional. Do not stop or alter your current course of treatment. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.

© 2020 Dr Khalid Rahman

Discussion

Sarahkhalid on February 19, 2020:

Wow!!! I like it a lot. Nice.