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Hepatitis B

Viral Hepatitis Type B

Hepatitis B is a form of viral hepatitis, caused by the hepatitis B virus, a member of the Hepadnavirus family. It is estimated that worldwide, more than 350 million people have chronic hepatitis B virus infection. The course of the disease may be extremely variable, depending on the patient’s age and immune status. Complications from hepatitis B include progression to hepatocellular carcinoma and cirrhosis. Immunization with hepatitis B vaccine is the most effective means of preventing infection and its consequences.

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Presentation

There is a wide spectrum of clinical manifestation of HBV infection, ranging from an asymptomatic state to mild acute infection to severe chronic disease. The patient may have anicteric hepatitis in which the patients are mostly asymptomatic and usually proceeds to chronic hepatitis. The other form is icteric hepatitis in which the patient may complain of low grade fever, anorexia, nausea, vomiting, myalgia, fatigue and altered sensation to smell and taste. Pain in the epigastric region or right upper quadrant pain might be present. Icterus indicated by yellowing of the sclera, nails and skin is common. The urine might become dark yellow too.

Physical examination and proper history are the guides to a correct diagnosis. Physical findings include low grade fever, jaundice which may last for months but may appear 10 days after constitutional symptoms, palmar erythema, spider naevi, mildly enlarged liver and spleen. Vasculitis may or may not be present. When cirrhosis develops one may find peripheral edema, ascites, icterus, caput medusa, variceal bleeding, testicular atrophy and gynaecomastia.

Patient with chronic hepatitis may be asymptomatic or may have same symptoms as an acute infection. Later in the disease, patient may present with mental confusion, decreased or no sleep, disturbed sleep, hepatic encephalopathy and even coma. They may also have gastrointestinal bleeding and ascites. Multi-organ affection manifests itself in the form of pleural effusion, hepato pulmonary syndrome, myocarditis, pericarditis, arrhythmias and diffuse intravascular coagulopathy (DIC) that can occur in fatal hepatitis.

Patient may develop aseptic meningitis, encephalitis, Guillain-Barré syndrome (GBS) in acute phase. Pancreatitis can also occur. Cutaneous manifestations are more common in women than men.

Easy Bruising
  • Signs of severe liver scarring (cirrhosis) may include: Ascites (accumulation of fluid and swelling of the abdominal cavity) Star-shaped vein pattern developing on the swollen belly Jaundice Itching Easy bruising and bleeding Chronic HBV infection can[sfcdcp.org]
  • Symptoms of severe liver damage include the symptoms of hepatitis B and generalized itching a longer than usual amount of time for bleeding to stop easy bruising swollen stomach or ankles spiderlike blood vessels, called spider angiomas , that develop[transplant.surgery.ucsf.edu]
Splenomegaly
  • Physical examination features are nonspecific but can include mild enlargement and slight tenderness of the liver, mild splenomegaly, and posterior cervical lymphadenopathy in 15% to 20% of patients.[clevelandclinicmeded.com]
Fever
  • The other form is icteric hepatitis in which the patient may complain of low grade fever, anorexia, nausea, vomiting, myalgia, fatigue and altered sensation to smell and taste.[symptoma.com]
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • Fever: Ask your doctor whether you can take Tylenol (acetaminophen). However, be sure not to take more than directed because Tylenol may harm the liver if the recommended dose is exceeded.[hepmag.com]
  • Look for anything that concerns you, such as signs of a severe allergic reaction, very high fever, or unusual behavior.[healthychildren.org]
Fatigue
  • Fatigue: In the acute phase, bed rest and low physical exertion may be advised.[hepmag.com]
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • The symptoms of this condition include: Nausea and vomiting Fatigue Loss of appetite General aches and pains Headaches Symptoms of jaundice (yellowing of the skin and eyes) People do not know they ate infected with Hepatitis A at first because symptoms[news-medical.net]
  • But in some, it could result in an illness with symptoms of fatigue, lost of appetite, dark urine and yellow discoloration of the eyes, lasting for several months and even death from liver failure.[liver.stanford.edu]
Dentist
  • It is important for carriers to inform their dentist and health care providers. How can hepatitis B be prevented? A safe and effective vaccine to prevent hepatitis B is available.[health.ny.gov]
  • If you are having any other medical treatment, visiting the dentist, having a tattoo, body piercing or acupuncture; you must let the practitioner know that you have hepatitis B so they can take precautions to protect themselves and others.[britishlivertrust.org.uk]
  • […] who injects drugs people who change their sexual partner frequently men who have sex with men male and female sex workers people who work somewhere that places them at risk of contact with blood or body fluids, such as nurses, prison staff, doctors, dentists[nhs.uk]
  • Tell your doctor and your dentist if you have hepatitis B. If you are pregnant and have hepatitis B, tell the doctor and staff who deliver your baby.[transplant.surgery.ucsf.edu]
Malaise
  • It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and death may occur. Chronic infection can lead to cirrhosis and/or hepatocellular carcinoma. Diagnosis is by serologic testing.[merckmanuals.com]
  • Symptoms of acute hepatitis B might include: Jaundice (yellowing of the skin and eyes) Nausea and vomiting Abdominal pain Dark urine Joint pain (arthritis) Loss of appetite Fever Malaise (feeling of ill health) Fatigue (feeling tired all the time) What[hhs.gov]
  • Common symptoms include malaise, fever, gastroenteritis, and jaundice (icterus).[mayomedicallaboratories.com]
  • These symptoms abate with the onset of jaundice, although anorexia, malaise, and weakness can persist.[clevelandclinicmeded.com]
Weight Loss
  • We report a 42-year-old male Han Chinese who received adalimumab (ADA) alone during his vasculitis relapse, manifesting with weight loss, ankle arthritis, testicular inflammation and new-onset hypertension.[ncbi.nlm.nih.gov]
  • If you are experiencing significant weight loss, you may be referred to a nutritionist or dietitian.[hepmag.com]
  • Patients may have no symptoms, or they may experience abdominal pain and swelling, an enlarged liver , weight loss , and fever .[medicinenet.com]
Nausea
  • Hunger can intensify nausea, so try eating a cracker or other small piece of food every hour or two. Ginger helps with mild to moderate nausea. Peppermint, chamomile or raspberry leaf tea may also alleviate nausea.[hepmag.com]
  • Symptoms of hepatitis B infection may include: Appetite loss Fatigue Fever, low-grade Muscle and joint aches Nausea and vomiting Yellow skin and dark urine (jaundice) Unfortunately with chronic hepatitis B (CHB), you may not experience any symptoms.[viread.com]
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • The symptoms of this condition include: Nausea and vomiting Fatigue Loss of appetite General aches and pains Headaches Symptoms of jaundice (yellowing of the skin and eyes) People do not know they ate infected with Hepatitis A at first because symptoms[news-medical.net]
Vomiting
  • If a patient has had a large amount of vomiting or has not been able to take in liquids, blood electrolytes may also be checked to ensure that the patient's blood chemistry is in balance.[emedicinehealth.com]
  • Symptoms of hepatitis B infection may include: Appetite loss Fatigue Fever, low-grade Muscle and joint aches Nausea and vomiting Yellow skin and dark urine (jaundice) Unfortunately with chronic hepatitis B (CHB), you may not experience any symptoms.[viread.com]
  • Feces, nasal secretions, sputum, sweat, tears, urine, and vomit have not been implicated in the spread of hepatitis B.[ccohs.ca]
Loss of Appetite
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • The symptoms of this condition include: Nausea and vomiting Fatigue Loss of appetite General aches and pains Headaches Symptoms of jaundice (yellowing of the skin and eyes) People do not know they ate infected with Hepatitis A at first because symptoms[news-medical.net]
  • Symptoms may include tiredness, loss of appetite, stomach discomfort and yellow skin. The virus is found in blood, semen, vaginal fluids and saliva.[health.gov.on.ca]
  • Symptoms include: Achy muscles or joints Stomach pain Loss of appetite Mild fever Loose stool ( diarrhea ) Lack of energy Constipation Yellowing of skin or whites of the eyes Being sick to your stomach Brown urine Next: Management and Treatment Cleveland[my.clevelandclinic.org]
Abdominal Pain
  • Hepatitis B Electron micrograph of hepatitis B virus Specialty Infectious disease , gastroenterology Symptoms None, yellowish skin , tiredness , dark urine, abdominal pain Hepatitis B at Curlie (based on DMOZ )[en.wikipedia.org]
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • By the time symptoms such as abdominal pain and/or abdominal distension appear, it is often too late for treatment to be effective. Therefore, it is very important to get screened to see if you are chronically infected.[liver.stanford.edu]
Diarrhea
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include: Achy muscles or joints Stomach pain Loss of appetite Mild fever Loose stool ( diarrhea ) Lack of energy Constipation Yellowing of skin or whites of the eyes Being sick to your stomach Brown urine Next: Management and Treatment Cleveland[my.clevelandclinic.org]
  • Symptoms include: Achy muscles or joints Stomach pain Loss of appetite Mild fever Loose stool ( diarrhea ) Lack of energy Constipation Yellowing of skin or whites of the eyes Being sick to your stomach Brown urine Cleveland Clinic is a non-profit academic[my.clevelandclinic.org]
  • Side effects of lamivudine include fatigue, muscle aches, fever and chills, sore throat, nausea, stomach pain or cramps, and diarrhea. Serious side effects are rare, occurring in less than 1% of people taking lamivudine.[clinicaltrials.gov]
  • Symptoms may include: Fatigue Mild fever Headache Loss of appetite, nausea and sometimes vomiting Stomach pain Diarrhea or constipation Muscle aches and joint pain Skin rash Yellowish eyes and skin (jaundice) that usually appears after other symptoms[smartsexresource.com]
Jaundice
  • You may also have jaundice, a yellowing of skin and eyes, dark-colored urine, and pale bowel movements. Some people have no symptoms at all. A blood test can tell if you have it. HBV usually gets better on its own after a few months.[medlineplus.gov]
  • Jaundice occurs when the infected liver is unable to get rid of certain colored substances, or pigments, as it normally does.[medical-dictionary.thefreedictionary.com]
  • Symptoms that can occur include mild fever, headache, fatigue, loss of appetite, nausea and vomiting, diarrhea, muscle and joint pain, abdominal pain, a skin rash, and jaundice.[emoryhealthcare.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and death may occur. Chronic infection can lead to cirrhosis and/or hepatocellular carcinoma. Diagnosis is by serologic testing.[merckmanuals.com]
Myalgia
  • The other form is icteric hepatitis in which the patient may complain of low grade fever, anorexia, nausea, vomiting, myalgia, fatigue and altered sensation to smell and taste.[symptoma.com]
  • Ecchymoses (2%) Gastrointestinal: Nausea (2% to 4%), vomiting (2%) Hematologic & oncologic: Change in WBC count (2%) Hepatic: Increased serum alkaline phosphatase (4%), increased liver enzymes (2%) Local: Pain at injection site (4%) Neuromuscular & skeletal: Myalgia[drugs.com]
  • An insidious onset of nausea, anorexia, malaise, and fatigue, or flulike symptoms, such as pharyngitis, cough, coryza, photophobia, headache, and myalgias, can precede the onset of jaundice. Fever is uncommon, unlike with hepatitis A infection.[clevelandclinicmeded.com]
  • Acute illness is clinically indistinguishable from other forms of hepatitis, and symptoms include fever, jaundice, malaise, anorexia, nausea and vomiting, abdominal pain (especially in the right upper quadrant), myalgia, and the passage of dark-coloured[immunise.health.gov.au]
Arthralgia
  • PAN include the following: Cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure) Renal (eg, hematuria, proteinuria, renal insufficiency) Gastrointestinal (GI) (eg, abdominal pain, mesenteric vasculitis) Musculoskeletal (eg, arthralgias[emedicine.medscape.com]
  • Patients with chronic infection spontaneously clear surface antigen at a rate of 0.5% per year. 6 Patients with chronic hepatitis B can develop extrahepatic manifestations, including arthralgias, mucocutaneous vasculitis, glomerulonephritis, and polyarteritis[clevelandclinicmeded.com]
  • Jaundice may be preceded by an acute febrile illness with arthralgia or arthritis and rash, most typical of hepatitis B. During recovery, malaise and fatigue may persist for many weeks.[immunise.health.gov.au]
Urticaria
  • Additional symptoms include rash, hives (urticaria), arthritis, and burning/tingling in the arms and legs (polyneuropathy).[poz.com]
  • Immune System Disorders Hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm, and urticaria have been reported within the first few hours after vaccination .[rxlist.com]
Dark Urine
  • Hepatitis B Electron micrograph of hepatitis B virus Specialty Infectious disease , gastroenterology Symptoms None, yellowish skin , tiredness , dark urine, abdominal pain Hepatitis B at Curlie (based on DMOZ )[en.wikipedia.org]
  • Symptoms include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, discolored (clay) bowel movements, joint pain and jaundice (yellowish skin or eyes). 1 About half of infected adults and children over the age of five will[nvic.org]
  • But in some, it could result in an illness with symptoms of fatigue, lost of appetite, dark urine and yellow discoloration of the eyes, lasting for several months and even death from liver failure.[liver.stanford.edu]

Workup

Patients may present with minimal to wide range of symptoms. Laboratory tests are done to confirm the diagnosis and include, liver function tests, liver enzyme studies like alanine amino transferace (ALT), asparate amino transferace (AST) which are 100 times higher (almost 1000-2000IU/ml) and are the hallmark of acute hepatitis. ALT is usually higher than AST but if AST is higher than ALT, then one must consider cirrhosis. Gamma glutamyl transpeptidase (GGT) and alkaline phosphate levels (ALP) are also elevated.

Complete blood count, platelet count, haematologic and coagulation tests are also done. Serologic tests to determine HBsAg, antibody to HBc and IgM are necessary to diagnose acute hepatitis. HBeAg and HBV DNA quantification should be done to know patient’s level of infection.

Radiographic tests include abdominal ultrasonography, CT scan and MRI to look for biliary obstruction as the echogenecity of the liver parenchyma increases.

Histologic testing is done by performing a liver biopsy especially for chronic hepatitis cases in which the findings show ground glass appearance of hepatocytes due to infiltration of viral cells. In acute phase, one can see dying hepatocytes with lymphocytic infiltration. Once the diagnosis is confirmed, an immediate treatment plan is necessary [7].

Leukopenia
  • Peripheral blood counts may show mild leukopenia, with or without relative lymphocytosis. Loss of HBsAg and the development of HBsAb signify recovery from the acute infection and the development of immunity ( Fig. 1 ).[clevelandclinicmeded.com]
Hepatocellular Carcinoma
  • Treatment aims at halting the progress of disease which causes liver failure and finally hepatocellular carcinoma.[symptoma.com]
  • Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Chronic hepatitis B (HBV) and C virus (HCV) infection causes liver cancer.[ncbi.nlm.nih.gov]
  • Most people are asymptomatic, although some will present with complications such as cirrhosis, hepatocellular carcinoma, or liver failure.[bestpractice.bmj.com]
  • To investigate the transmission routes of hepatitis B virus (HBV) in families with clusters of infection and unfavorable prognoses and to analyze the prevalence of liver cirrhosis (LC) or hepatocellular carcinoma (HCC) in the offspring of these families.Families[ncbi.nlm.nih.gov]

Treatment

The plan of action for treatment of hepatitis B is to take care of the acute cases by admitting them in the ICU. Patients with acute hepatitis should be given tenofovir disoproxil fumarate (TDF) or entecavir (ETV) as the first line of treatment. Biochemic tests should be done regularly to see the improvement.

National Institute of Health recommends nucleotide therapy for acute phase as well as for those fulminant phases in which complications like cirrhosis, fibrosis, HBV DNA positive and chronic HBV cases which reactivate during chemotherapy. Antiviral treatment is given using pegylated interferon and nucleotide analogues. Patient’s immunity is increased using immunotherapeutic intervention. The goal is to stop the progress of disease.

Patients with chronic hepatitis and eventually hepatic failure should be admitted in the hospital and considered for liver transplant in case the disease progresses to end stage [8] [9].

Vaccine or immunoglobulins should be administered to the newborn of a positive HBsAg mother. Also, if there is an accidental needle prick or contact with a material like blade of the infected person, then they should receive Hepatitis B immunoglobulin and first dose of Hepatitis B vaccine at the same time. These individuals should be kept under observation and regular blood tests should be done to check for the disease [10].

Prognosis

The prognosis is bad as nearly one million people die of hepatitis B globally every year. The fatal outcomes are those related to hepatocellular carcinoma and cirrhosis. Old age, low immunity, alcohol intake, infection, cirrhosis, thrombocytopenia and mutation in the core can increase the risk of HCC.

However, individuals who have negative HBe Antigen and in whom HBV DNA is not detected, have a good prognosis, as in their body the disease progresses slowly and their survival period prolongs. The complications are lesser as well [6].

Etiology

Hepatitis B is caused by the Hepatitis B Virus (HBV) which is a DNA virus. It is transmitted through the infected person via body fluids like blood, saliva, semen and vaginal secretion. Thus sharing of needles, blades, having a sexual contact with the infected person and procedures like blood transfusion and organ transplant can put one at the risk of catching the infection. It is also transmitted to the newborn via infected mother during labour.

Thus proper laboratory tests before any procedure are a must. Various genes are found to be associated with the disease; however the subject is still under research [1] [2] [3].

Epidemiology

It is seen more among people of black origin and persons of Hispanic or Asian origin. Individuals with high number of sexual partners, those who have cocaine, those with divorce or separated marital history, foreign birth and those with low education level are at risk of developing hepatitis B, according to a survey done by national health and nutrition examination survey III.

Sex distribution
Age distribution

Pathophysiology

Hepatitis B Virus is a spherical, double shelled particle with rods and spheres and it can withstand extremes of temperature. It is a DNA virus that encodes four genes: surface gene S, core gene C, e antigen, X gene and polymerase gene P. The surface gene encodes viral envelope. The core antigen encloses viral DNA and is found on hepatocytes during immune response. The ‘e antigen’ is a marker of viral replication. The X gene encodes protein that helps in viral replication; thus it is involved in carcinogenesis.

If after the treatment a person develops antibodies to HBsAg, it suggests that the patient has recovered from HBV infection. Also, if a person is vaccinated, he will show anti-HBsAg antibodies positive. If the person has anti-HBcAg antibody, it is suggestive of a previous infection with HBV and has high chances of recurrence as the virus is still present. Anti-HBeAg suggest non-replicative state if HBV DNA is not found. However, HBeAg negative strains have also emerged [4].

When the immune system recognizes HBV on the surface of hepatocytes, it releases cytokines and other antibodies. CD4, CD8 lymphocytes are activated and attack HBV. However, in this the liver is injured and can also get cirrhosed. The patient can develop hepatocellular carcinoma.

Once the virus has entered the host, the disease begins. There are five stages of disease progression:

Stage 1

The incubation period of HBV is 2-4 weeks during which the patient remains asymptomatic. It can even be decades for a new born. The virus replicates itself without any manifestation of symptoms or increase in aminotransferase levels. It is an immune tolerance stage.

Stage 2

This is an active immune stage wherein the body reacts by producing inflammatory changes. It lasts for 3 to 4 weeks and HBeAg can be identified in the serum. HBV DNA starts decreasing in the patients who are clearing the infection.

Stage 3

This is an inactive, chronic stage in which the replication of virus is slow or nil and anti-HBeAg antibodies are detected. However, HBsAg is still present in the serum.

Stage 4

This is chronic disease in which HBeAg-negative disease can occur.

Stage 5

This is a stage of recovery when no HBV DNA or HBsAg is detected in the blood and there are antibodies against HBV antigens.
It can cause polyarteritis nodosa which is a serious complication during the earlier course of disease. In the chronic stage, HBV infection can cause cirrhosis of liver, glomerular nephritis and hepatocellular carcinoma (HCC) [5].

Prevention

The disease is transmitted via body fluids hence people should be educated to not share needles, scissors and shaving blades. One must avoid sexual contact with multiple partners and use contraceptive measure like condoms in case of affected partner.

Hepatitis B is transmitted via mother to the child during delivery hence screening the mother during the pregnancy for Hepatitis B is a must [11]. If the newborn is born to hepatitis B mother he/she is given a hepatitis B immunoglobulin [HBIG] with hepatitis B vaccine within 12 hours of birth. They should then follow the recommended vaccination schedule for children [12].

Also candidates who donate blood or organs are screened for the presence of virus. Healthcare workers are given Hepatitis B vaccine as they have high chances of getting infected with the disease.

Summary

Hepatitis B is a common problem worldwide as one third of the global population is infected with Hepatitis B Virus (HBV). It is transmitted via body fluids.

The patient may remain asymptomatic for months before the clinical symptoms manifest. It is a disease of global concern and the vaccine against HBV is compulsory in nearly all the countries.

Patient Information

Hepatitis B is a viral disease which has affected almost the whole world. It is transmitted via contaminated blood, saliva, semen and vaginal secretion. People in contact with the affected patients should avoid sharing of blades, needles, shaving kit. One should refrain from having sexual contact with infected individuals. Mothers should be screened during pregnancy for Hepatitis B as it is transmitted to the child during the process of delivery.

Hepatitis B symptoms range from no symptoms to the dreaded liver cancer (hepatocellular carcinoma) which can cause death. Patient may complain of low grade fever, reduced appetite, muscular pain, jaundice, nausea, vomiting and pain in the right upper quadrant of abdomen.

Laboratory tests show altered liver function tests and blood counts. Treatment aims at halting the progress of disease which causes liver failure and finally hepatocellular carcinoma.

References

Article

  1. Thursz MR, Thomas HC, Greenwood BM, Hill AV. Heterozygote advantage for HLA class-II type in hepatitis B virus infection. Nat Genet. 1997 Sep;17(1):11-2.
  2. Jouanguy E, Lamhamedi-Cherradi S, Altare F, Fondanèche MC, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis. J Clin Invest. 1997 Dec 1;100(11):2658-64.
  3. Zhou J, Chen DQ, Poon VK, Zeng Y, et al. A regulatory polymorphism in interferon-gamma receptor 1 promoter is associated with the susceptibility to chronic hepatitis B virus infection. Immunogenetics. 2009 Jun;61(6):423-30.
  4. Gish RG, Locarnini S. Chronic hepatitis B viral infection. In: Yamada T, ed. Textbook of Gastroenterology. 5th ed. Oxford, UK: Blackwell Publishing; 2009:2112-38.
  5. Kuo A, Gish R. Chronic hepatitis B infection. Clin Liver Dis. 2012 May;16(2):347-69.
  6. Heidrich B, Serrano BC, Idilman R, Kabaçam G, et al. HBeAg-positive hepatitis delta: virological patterns and clinical long-term outcome. Liver Int. 2012 Oct;32(9):1415-25
  7. Papatheodoridis G, Buti M, Cornberg M, et al. For the European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012 Jul;57(1):167-85.
  8. Liaw YF, Leung N, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008 Sep;2(3):263-83.
  9. Sherman M, Shafran S, Burak K, Doucette K, et al. Management of chronic hepatitis B: consensus guidelines. Can J Gastroenterol. 2007 Jun;21 Suppl C:5C-24C.
  10. Kennedy PT, Lee HC, Jeyalingam L, Malik R, et al. NICE guidelines and a treatment algorithm for the management of chronic hepatitis B: a review of 12 years experience in west London. Antivir Ther. 2008;13(8):1067-76.
  11. Rajbhandari R, Chung RT. Screening for Hepatitis B Virus Infection: A Public Health Imperative. Ann Intern Med. 2014 Jul 1; 161(1):76-7.
  12. Chang MH, Chen CJ, Lai MS, Hsu HM, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997 Jun 26;336(26):1855-9.

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