Hepatitis B

INTRODUCTION

Section 2 of 10

Background: In 1965, Blumberg et al reported the discovery of the hepatitis B virus (HBV) surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the HBV virion. Since then considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus.

Hepatitis B is a worldwide health care problem, especially in developing areas. It has been estimated that one third of the global population has been infected by this virus. Approximately 350 million people are chronic carriers, and only 2% will spontaneously annually seroconvert. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of this disease.

HBV is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction resulting in either an acute symptomatic disease or one that is asymptomatic. Patients may become immune to HBV or develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC). Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates liver transplantation currently seems to be the only viable treatment for the latest stages of this disease.

Pathophysiology: Hepatitis B virus is a Hepadna virus. It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive when stored for 15 years at -20°C, for 24 months at -80°C, for 6 months at room temperatures, and for 7 days at 44°C. The viral genome consists of a partially double-stranded circular DNA of 3.2 kilobase pairs (kb) that encodes 4 overlapping open reading frames as follows:

• S for the surface or envelope gene encoding the pre-S1, pre-S2, and the S protein

   

• C for the core gene, encoding for the core nucleocapsid protein and the e antigen

   

• X for the X gene encoding the X protein

   

• P for the polymerase gene encoding a large protein promoting priming, RNA- and DNA-dependent DNA polymerase and RNase H activities.

It has been found that there is an upstream region for the S and C genes named preS and preC, respectively. The structure of this virion is a 42-nm spherical double-shelled particle consisting of small spheres and rods with an average width of 22 nm.

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: a, common to all HBsAg and d, y, w, and r, which are epidemiologically important. The core antigen, HBcAg, is the protein that encloses the viral DNA. It also can be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, comes from the core gene and is a marker of active viral replication. Usually the HBeAg can be detected in patients with circulating serum HBV DNA.

The best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum.

The role of the X gene is to encode proteins that act as transcriptional transactivators aiding the viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

The production of antibodies against HBsAg confers protective immunity and can be detected in patients recovered from HBV infection or in those who have been vaccinated. Antibody against to HBcAg is detected in almost every patient with previous exposure to HBV virus. The immunoglobulin, IgM subtype, is indicative of acute infection or reactivation, while the IgG subtype is indicative of chronic infection. With this marker alone one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state, and the antigen has been cleared.

With the newest PCR techniques, scientists are able to identify variations in the HBV genome (variant strains). A mutation at the 1896 nucleotide (precore/core region) processing the production of the HBeAg was identified first. The prevalence of this mutant virus varies among different areas. It has been estimated that 50-60% of the patients from southern Europe, the Middle East, Asia, and Africa and 10-30% of patients in the US and Europe who have chronic HBV have been infected by this strain.

The pathogenesis and clinical manifestations are due to the interaction of the virus and the host immune system. It is the latter that attacks the HBV and causes liver injury. Activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction is driven. Impaired immune reactions (eg, cytokines release, antibody production) or relatively tolerant immune status results in chronic hepatitis. There is, in particular, a restricted T cell–mediated lymphocytic response against the HBV-infected hepatocytes.

The final state of the disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop hepatocellular carcinoma. In the US, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission). Four different stages have been identified in the viral life cycle.

• First stage: Immune tolerance. The duration of this stage for the healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period often is decades. It is known that active viral replication continues despite little or no elevation in the aminotransferase levels and no symptoms of illness.

   

• Second stage: In this stage there is an inflammatory reaction with a cytopathic effect. HBeAg can be identified in the sera, and a decline of the levels of the HBV DNA is seen. The duration of this stage for patients with acute infection is around 3-4 weeks (symptomatic period), and for patients with chronic infection it will be 10 or more years until cirrhosis will develop.

   

• Third stage: During this stage the host can target the infected hepatocytes and the HBV. There no longer is viral replication and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and the aminotransferases are normal. In this stage an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.

   

• Fourth stage: The virus cannot be detected, and antibodies to various viral antigens have been produced. It has been postulated that different factors may influence the evolution of these stages such as age, sex, immunosuppression, and co-infection with other viruses.

Frequency:
 

• In the US: There are an estimated 200,000 new cases of HBV annually, and 1-1.25 million people are carriers. The prevalence of the disease is higher among African Americans, Hispanics, and patients of Asian origin. In addition, there is a higher carrier state among certain subpopulations such as the Alaskan Eskimos, the Asian Pacific islanders, and the Australian Aborigines. HBV accounts for 5-10% of chronic end-stage liver disease and for 10-15% of cases of hepatocellular carcinoma.

  HBV is blamed for 5000 deaths annually. The prevalence of the disease is low until the age of 12 but increases thereafter. The increased prevalence after the age of 12 can be associated with the initiation of sexual contact (the major mode of transmission), the number of the sexual partners, and the early age of the first intercourse. Additional risk factors identified in the National Health and Nutrition Examination Survey (NHANES) III survey are non-Hispanic black ethnicity, cocaine use, high number of sexual partners, divorced or separated marital status, foreign birth, and low educational level. After implementation of routine vaccinations of infants in 1992 and adolescents in 1995, it is expected that the prevalence of HBV will further decline.

• Internationally: The HBV carrier rate variation is 1-20% worldwide. This variation is related to differences in the mode of the transmission and the age at infection. The prevalence of the disease in different geographical areas can be characterized as follows:

   

  • Low-prevalence areas in which the rate is 0.1-2% (eg, Canada, western Europe, Australia, New Zealand)

     

  • Intermediate-prevalence areas in which the rate is 3-5% (eg, eastern and northern Europe, Japan, Mediterranean basin, Middle East, Latin and South America, central Asia)

     

  • High-prevalence areas in which the rate is 10-20%(eg, China, Indonesia, Sub-Saharan Africa, Pacific islands, Southeast Asia)

  In areas of high prevalence, the predominant mode of the transmission is perinatal, and the disease is transmitted during the early childhood vertically from the mother to the infant. In areas of intermediate prevalence, sexual, percutaneous, and via delivery are the major routes of the transmission. In the areas of low prevalence, sexual and percutaneous transmissions during the adulthood are the main modes of transmission.

  Vaccination programs implemented in highly endemic areas such as Taiwan seem to change the prevalence of the HBV. In Taiwan the seroprevalence declined from 10% in 1984 (before the vaccination program) to less than 1% in 1994 and the incidence of the hepatocellular carcinoma from 0.52 to 0.13%.

Mortality/Morbidity: An estimated 250,000 persons globally and 5000 in America will die annually due to chronic HBV infection.

Race: African Americans have a higher prevalence of the disease than do Hispanics or whites.

Sex: More cases occur in males than in females.

CLINICAL

Section 3 of 10

History: The spectrum of the symptomatology varies from subclinical hepatitis, icteric hepatitis, to hyperacute, acute, and subacute hepatitis during the acute phase and from asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma during the chronic phase.

• Acute phase: The incubation period range is 1-6 months.
  Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Patients with anicteric hepatitis have a higher tendency to develop chronic hepatitis.

  Icteric hepatitis: During the prodromal period, a serum sicknesslike syndrome can occur. A more constitutional symptomatology includes the following:

• Anorexia

   

• Nausea

   

• Vomiting

   

• Low-grade fever

   

• Myalgia

   

• Fatigability

   

• Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)

   

• Right upper quadrant and epigastric pain (intermittent, mild to moderate)

• Patients with hyperacute, acute, and subacute hepatitis may present with the following:

• Hepatic encephalopathy

   

• Somnolence

   

• Disturbances in sleep pattern

   

• Mental confusion

   

• Coma

• Patients with chronic hepatitis can be healthy carriers without any evidence of active disease; they are asymptomatic, as well.

• Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:

• Symptoms similar to those of acute hepatitis

• Fatigue

• Anorexia

• Nausea

• Mild upper quadrant pain or discomfort

• Hepatic decompensation

Physical: The finding of the physical examination varies according to the stage of the disease from minimal to impressive for patients with hepatic decompensation.

• Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:

• Low-grade fever

• Jaundice (10 day after the appearance of the constitutional symptomatology and lasting for 1-3 months)

• Hepatomegaly (mildly enlarged, soft liver)

• Splenomegaly (5-15%)

• Palmar erythema (rarely)

• Spider nevi (rarely)

• The physical examination of patients with chronic hepatitis B can reveal stigmata of chronic liver disease such as the following:

• Hepatomegaly

• Palmar erythema

• Spider angioma

• Patients with cirrhosis may have the following symptoms:

• Ascites

• Jaundice

• History of variceal bleeding

• Peripheral edema

• Gynecomastia

• Testicular atrophy

• Abdominal collateral veins (caput medusa)

WORKUP

Section 5 of 10

Lab Studies:
 

• Acute hepatitis B

  High levels of the aminotransferases (alanine [ALT], aspartate [AST]) at a range of 1000-2000IU/mL is the hallmark of the disease, although values such as 100 times more than the upper normal limit can be identified. Higher values are seen in patients with icteric hepatitis. ALT levels usually are higher than AST.

  The alkaline phosphatase may be raised, but usually no more than 3 times the upper normal limit.

  Albumin can be slightly decreased and the serum iron levels may be raised. In the preicteric period (before the appearance of jaundice) leukopenia (granulocytopenia) and lymphocytosis are the most common hematologic abnormalities, accompanied by a rise of the sedimentation rate.

  Anemia due to a shortened red blood survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding.

  Patients with severe hepatitis experience a prolongation of the prothrombin time.

  Several viral markers can be identified in the serum and the liver. HBsAg (Australian antigen) and the HBeAg (marker of infectivity) are the first markers that can be identified in the serum. HBcAb (IgM) follows.

  For patients who recover, seroconversion to HBsAb and HBeAb will be identified, and the HBcAb will be of the IgG class. Patients with persistent HBsAg for more than 6 months will develop chronic hepatitis.

• Chronic hepatitis B

• Healthy carriers: The levels of the aminotransferases ALT and AST are normal and the markers of infectivity (HBeAg and HBV DNA) may be negative. HBsAg, HBcAb of IgG type, and HBeAb also will be present in the serum.

• Chronic active hepatitis B

  Mild-to-moderate elevation of the aminotransferases (up to 5 times the upper normal limit) will be found. The ALT levels usually are higher than that of the AST. Extremely high levels for the ALT can be seen during exacerbation or reactivation of the disease and can be accompanied by impaired synthetic function of the liver (decreased albumin levels, increased bilirubin, and prolonged prothrombin time). The HBV DNA levels are high during this phase. HBsAg, HBcAb of IgG or IgM type in case of reactivation, will be identified in the serum.

  If the levels of AST are higher than that of ALT, the diagnosis of cirrhosis must be ruled out. Hyperglobulinemia is another finding, with an elevation of the IgG globulins predominantly. Tissue-nonspecific antibodies such as antismooth muscle (20-25%) or antinuclear (10-20%) antibodies can be identified. Tissue-specific antibodies such as antibodies against the thyroid gland (10-20%) can be found, as well. Mildly elevated levels of rheumatoid factor usually are present.

• Cirrhosis

  In early stages, findings of chronic viral hepatitis can be found. Later on, as the disease progresses low albumin levels, hyperbilirubinemia, prolonged prothrombin time, low platelet and white blood cell count, and AST levels higher than that of the ALT can be identified. The levels of the alkaline phosphatase and gamma glutamyl transpeptidase can be slightly elevated.

Imaging Studies:
 

• Acute hepatitis B

  Abdominal ultrasonography, CT scan, or MRI are important to exclude biliary obstruction. Nonspecific findings include an increased echogenicity of the liver parenchyma.

• Chronic hepatitis B

  Nonspecific findings such as increased echogenicity of the liver parenchyma

• Cirrhosis

• Coarse echogenicity of the liver with nodular appearance and findings compatible with portal hypertension such as varices, splenomegaly, ascites, pleural effusion (hepatic hydrothorax).

• Lesions can be detected and can be very difficult to evaluate, as they can be mistaken for regenerating nodules. For these cases, highly sophisticated techniques such as MRI with superparamagnetic iron oxide (ferumoxides) should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver producing a predominant T2 imaging at the MRI, and therefore there is a marked decrease of the signal of the normal liver parenchyma, effectively permitting the identification of tumors.

Procedures:
 

• Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease for patients with features of chronic active liver disease (abnormal aminotransferases and detectable levels of HBV DNA).

Histologic Findings: Although liver biopsy is not indicated for patients with acute hepatitis B, the findings are a lobular predominant picture with degenerative and regenerative hepatocellular changes and accompanying inflammation. Necrosis may be predominantly centrilobular.

Staging: Liver damage grading according to the inflammatory component is as follows:

• Grade 0 - Portal inflammation only, no activity

   

• Grade 1 - Minimal portal inflammation and patchy lymphocytic necrosis with minimal lobular inflammation and spotty necrosis

   

• Grade 2 - Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts with mild hepatocellular damage

   

• Grade 3 - Moderate portal inflammation and lymphocytic necrosis involving all portal tracts with noticeable lobular inflammation and hepatocellular change

   

• Grade 4 - Severe portal inflammation and severe lymphocytic bridging necrosis with severe lobular inflammation and prominent diffuse hepatocellular damage.

MEDICATION

Section 7 of 10

The goals of pharmacotherapy are to reduce morbidity, and prevent complications.

Drug Category: Antivirals -- Interferes with replication; weakens or abolishes viral activity

FOLLOW-UP

Section 8 of 10

Further Inpatient Care:
 

• Fulminant hepatic failure: Patients should be hospitalized in the intensive care unit and be enrolled for liver transplantation in case they fail to recover.

• Acute hepatitis: Patients should be monitored with blood tests in order to establish biochemical improvement.

Further Outpatient Care:
 

• Healthy carriers should have routine blood test to check the level of the aminotransferases annually

• Chronic active hepatitis: Blood tests (to evaluate the level of the aminotransferases, the antigen-antibody HBV profile and the viral load), liver biopsy and treatment should be suggested.

• Cirrhotic patients must be checked every 3-6 months with a-fetoprotein and abdominal ultrasound for HCC surveillance.

Deterrence/Prevention:
 

• Universal vaccination programs are ongoing in endemic areas, with encouraging results. This vaccine consists of recombinant HBsAg produced in yeast. A series of 3 injections may achieve HBsAb levels of greater than 10 million IU/mL in approximately 95% of the people vaccinated. Low response rates have been associated with obesity, smoking, immunosuppression, and advance age. HBV vaccine seems to be safe, although there are some questions about neurological complications.

• Approximately 25-50% of the nonresponders will respond to one additional vaccine dose and 50-75% will respond to a second 3-dose series.

• Vaccination with a single dose must be repeated every 5-10 years.

• All newborns must be vaccinated. For infants born to mothers with active HBV infection, a passive-active (immunoglobulin and vaccination) approach is recommended.

• A combined hepatitis A and B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time.

• Health care workers or people who have had a needle stick accident from a patient with active HBV infection must have an active-passive immunization approach (HBIG and the first dose of the vaccine at the same time) and must be followed up with blood tests.

Complications:
 

• Hepatocellular carcinoma

  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 HBV cirrhotics reported in Taiwan is 2.8%. It is estimated that in the US the annual incidence of HCC in HBV-infected patients is 818 per 100,000. Familiar clustering of HCC has been described among families with HBV in Africa, the Far East, and Alaska.

  The prevalence of HDV coinfection among HBV-infected patients worldwide varies between 0–20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated. The prevalence of anti-delta among cirrhotics with and without HCC was not significantly different. Therefore, delta superinfection does not appear to increase the rate for HCC.

  The prevalence of HCC among HBV and HCV coinfected patients is higher than with single infection alone. The rate of development of HCC per 100 person years of follow-up was 2.0 in cirrhotic patients with HBV, 3.7 in patients with HCV, and 6.4 for patients with dual infection. This points to a probable synergistic effect on the risk of HCC.

  The mechanism by which chronic HBV 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 multi-nucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell proliferation rate increases the risk for HCC.

  Facultative liver stem cells being 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 alpha fetoprotein. 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 increased risk for development of HCC. Although the presence of cirrhosis is found in the majority of these patients, it is not obligatory, as chronic carriers may develop HCC even without the evidence of cirrhosis.

  It is speculated that HBV has an 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 the normal DNA sequencing accompany integration. Transactivation of the function of genes controlling transcriptional factors (ie, insulin growth factor II, transforming growth factor-a, transforming growth factor-b, cyclin-a [a protein that controls cell division], epidermal growth factor-r, retinoic acid receptor) 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.

  Further, the integrated part of the HBV controlling the production of the HBxAg is over-expressed. These observations suggest that it is not the site of the viral genomic integration into the host’s DNA alone that is the factor. Most likely the HBxAg produced by these sequences is the transactivating factor, as it has been found that it binds to a variety of transcription factors such as the CREB and ATF-2, which alters their DNA-binding specificity. Thus, the ability of pX 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.

  Furthermore, it has been postulated that HBxAg binds to the C-terminus and inactivates the product of the tumor suppressor gene p53 and (1) sequesters p53 in the cytoplasm resulting in the abrogation of the p53 induced apoptosis (although there is a controversy about this concept), (2) reduces the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair as XPB and XPD, (3) reduces p21WAF1 expression, which is a cell cycle regulator, and (4) binds to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of HBV-infected patients altering its function.

  Tumor necrosis factor-a (TNF-a, proinflammatory cytokine) levels also are upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX, and the elevated levels of TNF-a, are responsible for the high levels of nitric oxide found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of p53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the preS/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 (GN) described is membranous (MGN), mainly in children, but membranoproliferative (MPGN) and, even more rarely, IgA nephropathy have been identified. The prevalence of GN among patients with chronic HBV infection is not well known, although there are observations made in children suggesting a range of 11-56.2%. Such a high prevalence, however, is not recognized in the US, and this may be because of the differences in epidemiology of HBV, which might be predominantly perinatal in other geographic areas of the world.

  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 HBV replicative state often are evident, and complement activation is suggested by low levels of C3 and C4.

  Generally, the most prominent finding among children is that of MGN with, mainly, capillary wall deposits of HBeAg. Adults, in contrast, present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy also has been described.

  The mechanism by which patients with chronic HBV develop GN is not completely understood. One possible explanation is that HBV antigens (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 (ISH) in the kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and epithelial cells of renal tubules.

  Interferon-a (INF-a) therapy has been successful in treating HBV related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It also has 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 patients but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation.

  The prognosis of the disease is related to several factors such as age and response to therapy. Children with MGN respond more favorably than adults. Whites respond better than Asians and blacks. Approximately 30-60% of patients with MGN undergo a spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas where HBV is endemic is not benign. Regardless of treatment, the 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

  There is an association between HBV and arteritis when the presence of HBsAg in serum and in the vascular lesions was described. Evidence for a cause-and-effect relationship is further supported by a high prevalence 36-69% of HBsAg in patients with PAN. This very serious complication presents early during the course of the disease and there is a high incidence among certain populations such as the Alaskan Eskimos. The pathogenesis of polyarteritis nodosa (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 that might trigger the onset of the disease, although it is uncertain if these represent the primary etiology of the disease.

  The clinical manifestations of the disease include cardiovascular (hypertension [sometimes severe], pericarditis, heart failure), renal (hematuria, proteinuria, renal insufficiency), gastrointestinal (abdominal pain, mesenteric vasculitis), musculoskeletal (arthralgias, arthritis), neurological (mononeuritis), and dermatological (rashes) involvement. Significant proteinuria (>1 g/day), renal insufficiency (serum creatinine >1.58 mg/dL), gastrointestinal involvement, cardiomyopathy, and CNS involvement are associated with increased mortality. The course of PAN is independent of the severity and the progression of the liver disease. 20-45% of these patients will succumb as a consequence of vasculitis in 5 years despite treatment and the mortality rate is similar for HBsAg seropositive and seronegative patients with PAN.

  Small and medium-sized arteries and arterioles are affected. Although corticosteroids and immunosuppressive agents may be beneficial in treating vasculitis, they potentially may have a deleterious effect on the course of HBV liver disease due to 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. Due to the fact that this is a rare complication, to date there has not been any experience published with the use of the newer therapies for HBV that include the nucleoside analogue, lamivudine.

• Skin manifestations

  A variety of cutaneous manifestations have already been recognized, among which are hives and fleeting maculopapular rash, during the early course of viral hepatitis. Women are more prone to developing cutaneous manifestations. The nature of the various cutaneous lesions is that they 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 infection, more commonly with acute infection in children.

• Cardiopulmonary manifestations

  Pleural effusion, hepatopulmonary, and portopulmonary syndrome in patients with cirrhosis; myocarditis, pericarditis, arrhythmia in patients with fulminant hepatitis, mainly

• Joint and neurologic manifestations

  Guillain Barré syndrome, encephalitis, aseptic meningitis, mononeuritis multiplex in patients with acute hepatitis; arthralgias, arthritis (serum sickness) subcutaneous nodules, (rarely)

• Hematologic and gastrointestinal tract manifestations

  Pancreatitis; aplastic anemia is uncommon, agranulocytosis extremely uncommon, diffuse intravascular coagulation (DIC) in patients with fulminant hepatitis

Prognosis:
 

• Approximately 9% of western European cirrhotic patients developed HCC due to HBV in a mean follow-up of 73 months. The probability of HCC appearance after 5 years of the establishment of the diagnosis of cirrhosis was 6%, and the probability of decompensation was 23%.

• Significant risk factors for carcinogenesis included 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 HBV cirrhotics reported in Taiwan is 2.8%. It is estimated that in the US the annual incidence of HCC in HBV-infected patients is 818 per 100,000. Familiar clustering of HCC has been described among families with HBV in Africa, the Far East, and Alaska. The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively.

• Cox's regression analysis identified 6 variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin, and HBeAg positivity at time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. No difference in survival of hepatitis D virus (HDV)-infected and uninfected patients was observed.

• The prevalence of HDV coinfection among HBV-infected patients varies worldwide between 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated, with controversial results. The prevalence of anti-delta among cirrhotics with and without HCC was not significantly different, although it has been reported that HDV infection increases the risk for HCC 3-fold and for mortality 2-fold in patients with HBV cirrhosis.