eMedicine Specialties > Gastroenterology > Liver

Hepatitis B: Follow-up

Author: Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Coauthor(s): K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
Contributor Information and Disclosures

Updated: Jun 19, 2009

Follow-up

Further Inpatient Care

  • Fulminant hepatic failure: Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU), and these individuals should be considered as liver transplant candidates in the event they do not recover.
  • Acute hepatitis: Patients should be monitored with blood tests in order to document biochemical improvement.

Further Outpatient Care

  • Inactive carriers of the hepatitis B virus (HBV) should have routine blood tests annually to check their aminotransferase levels.
  • Patients with chronic active hepatitis should undergo blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, and viral load), liver biopsy, and treatment.
  • Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein (AFP) measurements and abdominal ultrasonography for HCC surveillance.

Deterrence/Prevention

  • Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. The hepatitis B vaccine consists of recombinant HBsAg produced in yeast. A series of 3 injections may achieve HBsAb levels greater than 10 million IU/mL in approximately 95% of people vaccinated.
    • Low response rates have been associated with obesity, smoking, immunosuppression, and advanced age.
    • The HBV vaccine seems to be safe, although some questions exist regarding neurologic complications.
    • Approximately 25-50% of persons who initially do not have a vaccine response will show a response to 1 additional vaccine dose, and 50-75% of persons will have a response to a second 3-dose series.
    • Vaccination with a single dose must be repeated every 5-10 years.
    • All newborns must be vaccinated against hepatitis B. For infants born to mothers with active hepatitis B virus (HBV) infection, a passive-active (immunoglobulin and vaccination) approach is recommended.
    • A combined hepatitis A (HAV) and hepatitis B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time.
    • Healthcare workers or people who have had a needle-stick accident from a patient with active hepatitis B infection must receive the active-passive immunization approach (HBIG and the first dose of the vaccine at the same time), and these individuals must be monitored with blood tests.

Complications

  • HCC
    • Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with hepatitis B infection and cirrhosis reported in Taiwan is 2.8%. The estimated US annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska.
    • The prevalence of hepatitis D virus (HDV) coinfection among patients infected with hepatitis B virus (HBV) worldwide is 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different. Therefore, delta superinfection does not appear to increase the rate of HCC.
    • The prevalence of HCC among patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is higher than in those with a single infection alone. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and hepatitis B infection, 3.7% in patients with HCV infection, and 6.4% in patients with hepatitis B and C dual infection. This points to a probable synergistic effect on the risk of HCC.
    • The mechanism by which chronic hepatitis B infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors for nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk for HCC.
    • The fact that facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm. Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of AFP. Although the cellular targets of carcinogenesis have not been identified, some evidence resulting from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC. Although cirrhosis is found in the majority of these patients, it is not obligatory because chronic carriers may develop HCC even without the evidence of cirrhosis.
    • Hepatitis B virus (HBV) has been speculated to have intrinsic hepatocarcinogenic activity, interacting with host DNA in different ways. After entering the hepatocyte, viral DNA is integrated within the genome. The site of integration is not constant but usually involves the terminal repeat sequences. Chromosomal deletions, translocations, rearrangements, inversions, or even duplications of normal DNA sequencing accompany integration.
    • Transactivation of the function of genes controlling transcriptional factors (ie, insulinlike growth factor II [IGF-2], transforming growth factor-alpha [TGF-a], TGF-beta, cyclin-a [a protein that controls cell division], epidermal growth factor-r [EGFR], retinoic acid receptor [RAR]) and oncogenes such as c-myc, fos, ras (activating the internal signal transduction cascade upregulating ras/mitogen–activated kinase, c-Jun N terminal kinase, nuclear factor–kB, Jak-1-STAT, src- dependent pathways) influence the normal hepatocyte differentiation or cell cycle progression.
    • Furthermore, the integrated part of the hepatitis B virus (HBV) controlling the production of the HBxAg (antigen for the X gene of HBV) is overexpressed. These observations suggest the site of viral genomic integration into the host's DNA alone is not the factor. Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB and ATF-2, which alters their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.
    • Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53 and (1) sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept); (2) reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD; (3) reduce p21WAF1 expression, which is a cell cycle regulator; and (4) bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B infection, thus altering its function.
    • Tumor necrosis factor-alpha (TNF-a, a proinflammatory cytokine) levels are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-alpha are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc, and this upregulates the expression of TGF-a by transactivation.
  • Glomerulonephritis
    • The most common type of glomerulonephritis described in association with hepatitis B is membranous glomerulonephritis (MGN), mainly in children. However, membranoproliferative glomerulonephritis (MPGN) and, even more rarely, IgA nephropathy, have been identified. The prevalence rate of glomerulonephritis among patients with chronic hepatitis B infection is not well known, although observations have been made in children that suggest a range of 11% to 56.2%. However, such a high prevalence is not recognized in the United States, and this may be because of the differences in epidemiology of HBV, which might be predominantly perinatal in other geographic areas of the world (see Frequency, International).
    • A previous history of chronic liver disease is not present in the majority of these patients at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. Serologic markers of a hepatitis B virus (HBV) replicative state are often evident, and complement activation is suggested by low levels of C3 and C4.
    • Generally, the most prominent finding among affected children is MGN, primarily with capillary wall deposits of HBeAg. In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy has also been described.
    • The mechanism by which patients with chronic hepatitis B infection develop glomerulonephritis is not completely understood. One possible explanation is that hepatitis B virus (HBV) antigens (ie, HBsAg, HBeAg) act as triggering factors, eliciting immunoglobulins and thus forming immune complexes, which are dense irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and in the epithelial cells of renal tubules.
    • IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a SC daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation.
    • The prognosis of hepatitis B disease is related to several factors, such as age and response to therapy. Children with MGN have a more favorable response than adults. White persons have a better response than Asians and black patients. Approximately 30-60% of cases with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which the virus is endemic is not benign. Regardless of treatment, hepatitis B disease has a slow but relentlessly progressive clinical course in approximately one third of patients who have progressive renal failure, necessitating maintenance dialysis therapy.
  • Polyarteritis nodosa
    • An association between hepatitis B and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN). This very serious complication presents early during the course of hepatitis B disease, and the incidence is high among certain populations, such as Alaskan Eskimos. The pathogenesis of PAN is not clear. Circulating immune complexes containing HBsAg, immunoglobulins (IgG and IgM), and complement have been demonstrated by immunofluorescence in the walls of the affected vessels, which might trigger the onset of PAN. However, whether these represent the primary etiology of the disease remains unclear.
    • The clinical manifestations of PAN include cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure), renal (eg, hematuria, proteinuria, renal insufficiency), gastrointestinal (eg, abdominal pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis), neurologic (eg, mononeuritis), and dermatologic (eg, rashes) involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum creatinine >1.58 mg/dL), gastrointestinal and central nervous system involvement, and cardiomyopathy, are associated with increased mortality. The course of PAN is independent of the severity and the progression of the liver disease. Of these patients, 20-45% die as a consequence of vasculitis in 5 years, despite treatment, and the mortality rate is similar for patients with PAN who are HBsAg seropositive and for those with PAN who are seronegative.
    • Small and medium-sized arteries and arterioles are affected in PAN. Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they potentially may have a deleterious effect on the course of hepatitis B liver disease because of viral reactivation, particularly after the withdrawal of treatment. Adenine arabinoside, an antiviral drug, and IFN-a, an immunomodulator and antiviral protein, have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results. Because of the fact that this is a rare complication, to date no reports have been published on the use of the newer therapies for HBV and PAN that include the nucleoside analogue lamivudine.
  • Skin manifestations
    • A variety of cutaneous manifestations have already been recognized during the early course of viral hepatitis, among which are hives and a fleeting maculopapular rash. Women are more prone to developing cutaneous manifestations.
    • The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities.
    • Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B disease, more commonly with acute infection in children.36
  • Cardiopulmonary manifestations
    • Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis.
    • Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis.
  • Joint and neurologic manifestations
    • Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B disease.
    • Arthralgias and arthritis (serum sickness) subcutaneous nodules may also occur, but these are rare.
  • Hematologic and gastrointestinal tract manifestations

Prognosis

  • Approximately 9% of patients in western Europe who have cirrhosis develop HCC due to hepatitis B infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis is established is 6%, and the probability of decompensation is 23%.
  • Significant risk factors for carcinogenesis include older age, liver firmness, and thrombocytopenia. Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with hepatitis B infection and cirrhosis reported in Taiwan is 2.8%. The US estimates for the annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B infection in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% at 5 years and 68% at 10 years.
  • Cox regression analysis has identified 6 variables that independently correlate with survival. These include age, albumin level, platelet count, splenomegaly, bilirubin level, and HBeAg positivity at the time of hepatitis B diagnosis. According to the contribution of each of these factors to the final model, a prognostic index has been constructed that allows calculation of the estimated survival probability. No difference in survival is observed in patients with HDV infection compared with those who are not infected.
  • The prevalence of HDV coinfection among patients infected with hepatitis B virus (HBV) varies worldwide from 0% to 20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated, with controversial results. The prevalence of anti-delta among patients with cirrhosis with and without HCC is not significantly different, although HDV infection has been reported to increase the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis.

Miscellaneous

Medicolegal Pitfalls

  • Failure to identify cases of hyperacute fulminant hepatic failure and failure to list the patient as a candidate for liver transplantation
  • Failure to monitor healthy carriers for probable disease reactivation
  • Failure to inform the patients' spouses and sexual partners about the infectivity of hepatitis B disease and their possible need for vaccination
  • Failure to monitor patients with cirrhosis and failure to perform HCC surveillance studies (ie, AFP levels and liver ultrasonography) every 3-6 months
  • Failure to put patients with cirrhosis on liver transplantation lists when needed
  • Failure to identify HDV superinfection
 


More on Hepatitis B

Overview: Hepatitis B
Differential Diagnoses & Workup: Hepatitis B
Treatment & Medication: Hepatitis B
Follow-up: Hepatitis B
Multimedia: Hepatitis B
References
Further Reading
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Further Reading

Additional resources on hepatitis B are available at Medscape’s Hepatitis B Resource Center.

Related eMedicine Topics

Clinical Trials

National Guideline Clearinghouse

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Keywords

hepatitis B, hepatitis, HBV, hepatitis B infection, viral hepatitis, hepatitis B virus, chronic hepatitis, acute hepatitis, cirrhosis, fulminant hepatitis, hepatocellular carcinoma, HCC, extrahepatic manifestations, hepatitis D virus, HDV, delta virus, hepatitis C virus, HCV, hepatitis B surface antigen, HBsAg, Australia antigen, hepatitis B surface antibody, HBsAb, orthohepadnavirus, hepadnaviridae infection,

liver transplantation, liver transplant, OLT, interferon-alpha, IFN-a, peginterferon-alfa 2a, pegylated IFN-a 2a, lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir

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Contributor Information and Disclosures

Author

Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Nikolaos T Pyrsopoulos, MD, PhD, FACP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Liver Foundation, American Medical Association, American Society of Gastrointestinal Endoscopy, American Society of Transplantation, International Liver Transplantation Society, and Transplantation Society
Disclosure: Gilead Sciences Honoraria Speaking and teaching; Schering-Plough Honoraria Speaking and teaching; Roche Honoraria Speaking and teaching

Coauthor(s)

K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
K Rajender Reddy, MD, FACP, FACG is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and Florida Medical Association
Disclosure: Nothing to disclose.

Medical Editor

George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine
George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians
Disclosure: Humana Press Consulting fee Consulting; Novartis Consulting fee Review panel membership

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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