Hepatitis B. Pathology Research Report By: Hannah Matthews Spring Abstract

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1 Hepatitis B Pathology Research Report By: Hannah Matthews Spring 2016 Abstract The hepatitis B virus (HBV) is an infectious virus that causes inflammation and infection of the liver. This injury to the liver is caused by the body's immune response as the body attempts to eliminate the virus. Some people with hepatitis B never clear the virus and are chronically infected. It is one of the most infectious diseases in the world. Many of these people appear healthy but can spread the virus to others. Hepatitis B infection is transmitted through sexual contact, contact with contaminated blood and other bodily fluids, and from mother to child. Blood tests can identify the stage of the infection (past or present) and people who are at highest risk for complications. Chronic hepatitis B may lead to cirrhosis or liver failure. Hepatitis B is preventable through vaccination. All children should receive the vaccine. In addition, adults at high risk for hepatitis B should be vaccinated. Several manifestations of hepatitis B infection are seen in the oral cavity. These include Sjögrens syndrome, lichen planus, sialadenitis, and some forms of oral cancer. Cirrhotic patients may have thrombocytopenia (platelet deficiency) due to interferon treatment or hypersplenism. This platelet deficiency can manifest as petechiae or excess bleeding with gingival manipulation.

2 Introduction Hepatitis is the general term for inflammation of the liver. This inflammation most often arises from one of the five main types of hepatitis viruses, but it can also be caused by alcohol, drugs, or autoimmune diseases. Hepatitis B virus can lead to chronic infection, progressing to liver cirrhosis and cancer. Hepatitis B is primarily a blood born infection. Hepatitis B can cause both an acute and chronic infection. The initial infection may range from subclinical hepatitis to visible jaundice to fulminant hepatitis. In the chronic state, the disease remains infectious and transmittable for many years. While acute hepatitis rarely results in death, cirrhosis or hepatocellular carcinoma (liver cancer) may eventually develop. These complications result in the death of about 20% of those with chronic Hepatitis B infection. According to the World Health Organization (WHO), over 750,000 people die of hepatitis B each year and about 300,000 of these deaths are due to liver cancer. 2 When hepatitis is asymptomatic, the patient may unknowingly transmit the disease. Hepatitis B is preventable through a highly effective vaccine. Etiology & Pathology Hepatitis B virus (HBV) is transmitted from exposure to infectious blood and other body fluids. Possible transmissions include sexual contact, blood transfusions, re-use of contaminated needles, and from mother to child during childbirth. Vectors of infection with hepatitis B in the dental office include saliva, blood, and nasopharyngeal secretions. Someone who works with or is in contact with human body fluids is at risk for infection. These include emergency, dental, and medical personnel who are in contact with bodily fluids on a daily basis. Although HBV is still a concern in North America and Europe, the rates are now less than 1%. The disease is now most prevalent in Eastern Asia and sub-sahara Africa where between 5 and 10% of adults have chronic hepatitis B. The virus can be detected in the blood within 30 to 60 days after infection with an average incubation period of 75 days. Hepatitis B can present itself as an acute or chronic infection. Acute infections can last up to six months and is infectious during this stage. During the acute infection, the tests that are positive include Hepatitis B surface antigen (HBsAg), HBc-IgM, and sometimes the HBe-antigen. If the patient has a strong immune system the infection will resolve leaving the person with lifelong immunity. In contrast, a patient with a weak immune response will be more likely to develop chronic hepatitis B. In this case the hepatitis virus continues to replicate and remains infectious. Hepatitis B virus life cycle is complex. In order to replicate and gain access to the host cell, the virus binds to sodium/bile acid cotransporter (NTCP) on the surface and is endocytosed. The virus multiplies via RNA made by the host cell. In order to do so the partially double stranded viral DNA must transfer into the host cell s nucleus by host proteins called chaperones. In the

3 nucleus, the viral DNA is made fully double stranded and is covalently closed into circular DNA via viral polymerase. This circular DNA is then used for transcription of the viral RNA. During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The host immune response contributes to most of the liver injury associated with HBV infection. The most prominent immune response is virus-specific cytotoxic T lymphocytes (CTLs). CTLs eliminate the infection by killing infected cells and producing antiviral cytokines. Persistent infection causes chronic liver cell injury, inflammation, widespread DNA damage and deregulation of cellular growth control genes, which, collectively, lead to cirrhosis of the liver and often hepatocellular carcinoma. Epidemiology The earliest record of an epidemic caused by hepatitis B virus was in 1885 in Bremen, Germany. Hepatitis B is one of the world s most common infectious diseases. National prevalence ranges from over 10% in Asia to under 0.5% in North America and Europe. Routes of infection include vertical transmission through childbirth or horizontal transmission through sexual contact, bodily secretions, or intravenous drug use. In areas of low prevalence such as North America and Western Europe, injection drug abuse and unprotected sex are the primary methods of transmission (Figure 1). Highest incidence of the disease is seen in younger populations, those who are sexually promiscuous, or recreational drug users. In contrast, in areas of high prevalence such as China, South East Asia, and Africa, transmission during childbirth is most common. According to World Health Organization (WHO), over 750,000 people die every year related to this infection. 2 Figure 1. Countries where the prevalence of chronic hepatitis B is the highest

4 Clinical Presentation Most individuals who are infected with hepatitis B virus are asymptomatic or have only mild symptoms that may delay motivation to receive treatment. Symptoms begin after the incubation period, which is 30 to 80 days. During the prodromal phase of the infection, individuals may develop a rapid onset of sickness with vomiting, tiredness, dark urine and abdominal pain. These symptoms last only a few weeks and the initial infection rarely results in death. The liver becomes inflamed, causing abdominal pain and the liver enzymes begin to rise. Once the disease has progressed into what is called the icteric phase, jaundice develops and the liver becomes tender. Hepatocellular jaundice can be caused by either acute or chronic hepatitis. This occurs due to the necrosis of cells in the liver, reducing its ability to metabolize and excrete bilirubin, leading to a buildup of unconjugated bilirubin in the blood. This buildup of bilirubin in the blood causes the skin to have a yellow hue. If the infection persists in a chronic state patients may progress to cirrhosis or hepatocellular carcinoma (liver cancer) and finally death. Several manifestations of hepatitis B infection are seen in the oral cavity. These include Sjögrens syndrome, lichen planus, sialadenitis, and some forms of oral cancer. Cirrhotic patients may have thrombocytopenia (platelet deficiency) due to interferon treatment or hypersplenism. This platelet deficiency can manifest as petechiae or excess bleeding with gingival manipulation. Diagnosis Hepatitis B virus is detected and diagnosed through tests called assays. These assays involve the detection of either viral antigens or antibodies produced by the host in response to the vital antigens. The hepatitis B surface antigen (HBsAg) is the most used to screen for the presence of this infection because it is the first detectable antigen to appear. The disadvantage of screening for HBsAg is that it may not be present in early infection and may be undetectable later in the infection, as it is being cleared by the host. This is the primary detection method for those with chronic carrier HBV. HBV carrier patients are those who remain HBsAg positive for at least six months. A person negative for HBsAg but positive for its antibody has either cleared the infection or has been vaccinated prior to the blood test. After HBsAg, another antigen called hepatitis B e antigen (HBeAg) will appear. This antigen is associated with high rates of viral replication and enhanced infectivity. Some strains of HBV do not produce HBeAg, but when these antigens appear in the serum the host is highly infective. The infectious virus has an inner core particle containing the viral genome, also known as hepatitis B core antigen (HBcAg). Once the infection has cleared IgG antibodies to the core antigen will appear. A blood test can

5 detect both IgM and IgG antibodies of the hepatitis B core antigen. IgM antibodies are produced first in response to the infection, while IgG antibody production follows in response to the core antigen. The Polymerase Chain Reaction test (PCR) is another test that detects and measures the amount of hepatitis B viral DNA in clinical specimens. This viral load test is used to assess a person s infectious status and to monitor treatment. Medical doctors assess the symptoms, medical history and perform blood tests to diagnose hepatitis B virus. The only true diagnosis is accomplished through blood tests to check for HBV antigens or antibodies. Liver biopsies can also be used to assess chronic HBV (Figure 2). Treatment Figure 2. Ground glass hepatocytes as seen in a chronic hepatitis B liver biopsy The best treatment of hepatitis B is preventing the virus from infecting the host in the first place with the HBV vaccine. The vaccine is most effective in children and, since 1991, has been routinely recommended for infants in the United States. The vaccine is usually given as 3 injections over a 6-month period. The body responds to the vaccine by producing antibodies against HBsAg. The concentration of the antibodies must be at least 10mlU/ml in the recipient s serum to be considered protective. Verification of the effectiveness of the immunization is recommended and further doses of the vaccine are given if the concentration is not sufficient. Once the antibodies have been accumulated and stored in the body they will fight off any future infection of the hepatitis B virus. Another form of prevention of transmission is by reducing the individual s risk factors. These include protection before having sexual intercourse, avoid sharing contaminated needles for drug use, assure that piercing and tattoo equipment is properly sterilized, and avoid sharing personal items with others. Healthcare professionals must be extra cautious due to the constant exposure to bodily fluids. They should be vaccinated against hepatitis B and follow standard infection control precautions. Treatment is usually not necessary during acute hepatitis B infection and is usually cleared by the host cells spontaneously. Early antiviral therapy may be required for those with aggressive HBV or those who are immunocompromised. For chronic infection, treatment may be necessary to reduce the risk for cirrhosis and liver cancer. Treatment lasts from six months to a year, depending on the medication. None of the available drugs can completely clear the infection, but they can stop viral replication, thus minimizing liver damage. Interferon, Lamivudine, Telbivudine, Entecavir, Adefovir, and Tenofovir are approved drugs used for the treatment of hepatitis B (Table 1). According to the World Health Organization, a combination of

6 tenofovir and entecavir are recommended as first line agents. Liver transplantation is a viable option for those whose livers are unable to be stabilized and don t function properly. Those with chronic hepatitis B should avoid other liver damaging products such as alcohol, certain medications, and some dietary supplements. Drug Name Action Dental Considerations Entecavir (Baraclude) - All ages for chronic HBV -None Tenofovir (Viread) - Patients over 2 years old for chronic HBV - Back pain (difficulty sitting in the dental chair) Interferon (Pegasys) - Immune system modulators - Chronic HBV and HCV -Xerostomia -Increased bleeding - Shortness of breath Telbivudine (Sebivo) - Viral replication -Joint pain (TMJ) Adefovir (Hepsera) -Viral replication -None Lamivudine (Epivir) - Viral replication -Active liver inflammation -None Table 1. Medications used to treat Hepititis B, and their mechanism of actions. 9 Implications for Dental Hygiene Care The most important dental hygiene consideration for those with hepatitis B virus is disease transmission. Most dental procedures require contact with saliva and blood, making it a prime environment for disease transmission. It is important for dental professionals to be aware of these infections and their symptoms as well as the modes of transmission. It has been found that HBV exists on various surfaces in the dental operatory and remains viable at room temperature for many days after treating patients with hepatitis B. Standard infection control precautions should be used when seeing all patients in the dental office because many patients will be unaware they have the virus or be unwilling to share that information. Hepatitis B infection may also manifest in the oral cavity. The dental hygienist should recognize Sjögrens syndrome, lichen planus, sialadenitis, and some forms of oral cancer (Figure 2 and 3). Cirrhotic patients may have thrombocytopenia (platelet deficiency) due to interferon treatment. This platelet deficiency can manifest in the oral cavity as petechiae or excess bleeding with gingival manipulation. The liver produces clotting factors that Figure 2. Lichen Planus Figure 3. Sialadenitis

7 may increase bleeding when dental hygiene treatment is completed and should be monitored. Xerostomia may be a sign of hepatitis B or of the treatment by interferon. The salivary glands are essential for lubrication, mastication, immunity and remineralization for demineralized enamel structures. For patients with xerostomia it is important to apply fluoride and advise them to use salivary flow stimulation. Conclusion Hepatitis B is a common yet preventable infectious disease affecting many areas all over the world. Hepatitis B virus is transmitted via bodily fluids such as blood and saliva. In order to prevent transmission, a hepatitis B vaccine is widely available. Hepatitis B liver damage can also reduce the clotting ability of blood and may have oral manifestations that should be recognized by the dental hygienist. Preventive oral hygiene measures must be implemented to reduce the need for dental surgical treatments. Many individuals with the virus are embarrassed, but dental hygienists should make it a priority to make all patients feel comfortable and welcome to request dental hygiene care.

8 References 1. Adrienne B. Viral Hepatitis [Internet]. c20 5 [cited 20 6 May 3]. Available from: emedicine.medscape.com 2. World Health Organization. Hepatitis B [Internet]. c20 5 [cited 20 6 May 5]. Available from: 3. Chisari FV, Isogawa M, Wieland SF. Pathogenesis of Hepatitis B Virus Infection. Pathologie-biologie. 20 0;58(4): doi: /j.patbio John M. Hepatitis: What Every Dental Professional Needs to Know [Internet]. c20 5 [cited 20 6 May 5]. Available from: CE Setia S, Gambhir S, Kapoor V. Hepatitis B and C Infection: Clinical Implications in Dental Practice. European Journal of General Dentistry. 20 3;2( ): Darby ML, Walsh MM. Dental Hygiene: Theory and Practice. 4th ed. St. Louis, Mo: Saunders/Elsevier; Locarnini, Stephen, et al. "Review: Strategies To Control Hepatitis B: Public Policy, Epidemiology, Vaccine And Drugs." Journal Of Hepatology 62. Supplement (20 5): S76-S86. ScienceDirect. 8. Nikolaos P, Rajender R. Hepatitis B Treatment & Management. Medscape [Internet]. c20 5 [cited 20 6 May 5]. Available from: emedicine.medscape 9. Wynn RL, Meiller TF, Crossley HL, editors. Drug information handbook for dentistry. 9th ed. Hudson (OH): Lexicomp; 20 5.