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Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It is a major global health problem and the most serious type of viral hepatitis. It can cause chronic liver disease and puts people at high risk of death from cirrhosis of the liver and liver cancer. The hepatitis B virus is transmitted through contact with the blood and body fluids of someone who is infected.Worldwide, an estimated two billion people have been infected with the hepatitis B virus (HBV), and more than 350 million have chronic (long-term) liver infections.
Hepatitis B is endemic in China and other parts of Asia. Most people in the region become infected with HBV during childhood. In these regions, 8% to 10% of the adult population are chronically infected. Liver cancer caused by HBV is among the first three causes of death from cancer in men, and a major cause of cancer in women. High rates of chronic infections are also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and Indian sub-continent, an estimated 2% to 5% of the general population is chronically infected. Less than 1% of the population in western Europe and North American is chronically infected.
The infection of HBV has two phases: acute and chronic
Acute (new, short-term) hepatitis B occurs shortly after exposure to the virus. A small number of people develop a very severe, life-threatening form of acute hepatitis called fulminant hepatitis.
Chronic (ongoing, long-term) hepatitis B is an infection with HBV that lasts longer than 6 months. Once the infection becomes chronic, it may never go away completely.
About 90-95% of people who are infected are able to fight off the virus so their infection never becomes chronic. Only about 5-10 percent of adults infected with HBV go on to develop chronic infection.
HBV infection is one of the most important causes of infectious hepatitis.
Structure Of HBV
The hepatitis B virus is a coated,circular,double stranded DNA molecule, with a (+) partial overlapping strand ; the minus strand has a length of approx.3.2 kilobases. This virus with a diameter of 42nm is classified as a hepadnavirus of the orhtohepadnavirus family.The hepatitis B virus (HBV) consists of a central core containing the core antigen(HBcAg) and a surrounding envelope containing the surface antigen (HBsAg),DNA, hepatitis Be antigen (HBeAg), and an enzyme (DNA polymerase)required to help the DNA reproduce are also located in the central core. The intact virusparticle containing these components is referred to as the "Dane particle" and is considered the infectious virus.
Tests for Diagnosing and Tracking Hepatitis B
The diagnosis of hepatitis relies on blood tests that either detect the virus in the bloodstream (viral load) or detect antibodies manufactured in response to infection. In addition, tests of liver enzymes are used to track treatment progress among people who have chronic hepatitis B. A liver biopsy is performed, not for diagnosis, but to grade the severity of liver disease.
Testing for hepatitis B includes evaluation of the following:
Hepatitis B surface antigen (HBsAg). This is the first test to show a positive result with acute hepatitis B infection. The level of the antigen rises before symptoms begin and then returns to normal when the jaundice disappears. A person is considered to be a carrier of hepatitis B if this antigen persists in the blood 6 months after the initial infection. In rare cases, a person with hepatitis B who was initially a carrier of the disease may eventually become a noncarrier and thus have life long immunity (that is, he or she may be a "late seroconverter" of surface antigen).
Antibody to HBsAg (anti-HBs). Its presence usually indicates immunity against hepatitis B (the person has previously had hepatitis B, recovered, and is now immune, or has been vaccinated against hepatitis B and is now immune.) People who have a positive test result for this antibody will not develop a hepatitis B infection again. Hepatitis B immune globulin (HBIG) becomes detectable about 6 months after an acute hepatitis B infection and will remain in the blood for life, although its level will decrease over many years. To prevent hepatitis B, doctors inject super-concentrated antibody HBIG into people who have been exposed to the disease.
Hepatitis B e antigen (HBeAg). Presence of this antigen indicates that the person is highly infectious and that the virus is replicating. The antigen is found during the time of early symptoms of acute hepatitis. Persistent levels of HBeAg indicate a chronic infection.
Antibody to HBeAg (anti-HBe). The presence of anti-HBe indicates that infectivity is decreasing and that the period of high infectivity is ending.
Antibody to hepatitis B core antigen (anti-HBc). This antibody appears about 1 month after acute infection. Its level declines very gradually over many years. It is also present in people who have chronic hepatitis. During the time lag between the disappearance of HBsAg and the appearance of hepatitis B surface antibody (HbsAb)/anti-HBs, core antibody is elevated. This elevation, called the "core window," may be the only marker that indicates a recent hepatitis infection.
Viral load. In a person who has the hepatitis C virus (HCV) or one who has chronic hepatitis B, the viral load is measured by the quantitative HCV polymerase chain reaction (PCR) laboratory test. PCR refers to the type of assay used in the test. The result is reported in number of copies of the virus. Quantitative HCV PCR is used to measure a patient's response to treatment.
Liver function. An elevation in the results of some liver function tests, particularly the transaminases (found on routine blood chemistry testing), should prompt the physician to order a hepatitis screening panel, which would include screening tests for hepatitis B and other forms of hepatitis.
Extrahepatic manifestation of Hepatitis B
Numerous extrahepatic manifestations have been reported in patients with both acute and chronic hepatitis B (arthralgias or arthritis, skin rashes, glomerulonephritis and neuritis), all of which are present in polyarteritis nodosa (PAN) which is the most unique and spectacular extrahepatic manifestation of HBV. In the 1970s, the frequency of PAN due to the hepatitis B (HBV) reached 30%. Immunization programs explain the decrease and it is now down to 7%. PAN usually occurs within 6 months of infection.
Clinical manifestations reflect this most classic form of PAN, Hepatic manifestations including, ALT/AST elevations are mild and usually overlooked. Besides HBV, other viruses may be responsible for cases of vasculitis including PAN, HIV, Parvovirus B19, and EBV. Different pathogenic mechanisms have been identified but immune complexes are mainly thought to be responsible.
Other most common form of extrahepatic manifestation of HBV is glomerulonephritis. In glomerulonephritis, detailed immunostaining and ultrastructural findings indicates that HBe antigen (Ag) is more likely to be the responsible antigen.
In PAN, fewer reports are available and early studies with poorly defined antibodies need to be revisited. Interestingly almost all cases of HBV/PAN are associated with wild-type HBV infection, characterised by HBe antigenemia and high HBV replication, supporting the concept that lesions could result from the deposit of viral Ag/Ab complexes soluble in Ag excess, possibly involving HBe Ag. The recent observation of PAN cases associated with precore mutation which abrogates the formation of HBe Ag challenges this view. It may suggest that other, still undefined, circulating HBV-related Ag(s) distinct from HBe Ag could be involved.
Remarkably, none of the HBV/PAN cases or glomerulonephritis exhibit antineutrophil cycoplasmic antibodies (ANCA) reactivity. Viral PAN can now be completely separated from other form of vasculitis mostly autoimmune in nature. Based on the efficacy of antiviral agents in chronic hepatitis B and of plasma exchanges in PAN we combined both therapies to treat HBV PAN.
This was associated with swift recovery, even in the most severe forms. The perfect time correlation between inhibition of virus replication and resolution of all bioclinical signs suggest a direct pathogenic role of the virus possibly via immune complexes. Traditional immunosuppressive and steroid therapy should no longer be used for HBV PAN cases.
Others forms of extrahepatis manifestations of HBV can also be found in patients such as Serum sickness liked syndrome,essential mixed cryoglobulinemia, dermatologic manifestations ,arthritic and nerologic manifestations.
Polyarteritis Nodosa(PAN) Associated with HBV
Polyateritis nodosa (PAN) is a rare complication of hepatitis B virus infection developing in about 1-5% of patients with hepatitis B . On the otherhand, hepatitis B virus infection accounts for around 30% of polyarteritis nodosa cases.
Definition of PAN
Polyarteritis nodosa (PAN) is a rare autoimmune disease characterized by spontaneous inflammation of the arteries (arteritis) of the body. Because medium sized arteries are involved, the disease can affect any organ of the body. The most common areas of involvement include the muscles, joints, intestines, nerves, kidneys, and skin. Kussmaul and Meier first described polyarteritis nodosa in 1866.
Stages of PAN
1.Acute stage: Polymorphonuclear neutrophils infiltrate all layers of the vessel wall.
2.Subacute stage: Infiltration of mononuclear cells becomes more prominent.
3.Chronic stage: Fibrinoid necrosis of the vessels causes thrombosis and tissue infarction. Aneurysmal dilatations of the involved arteries, as large as 1 cm in size, are characteristic findings of PAN.
Immunopathogenetic mechanisms leading to vascular injury are incompletely understood and are probably heterogeneous. Some of the possible mechanisms follow.
The origin of the immune complex is unknown. Various infections and superantigens have been implicated as causes of persistent antigenemia that subsequently leads to immune complex formation. The resultant immune complex activates the complement cascade, which activates and attracts neutrophils.
Antineutrophil cytoplasmic antibodies
Antineutrophil cytoplasmic antibodies (ANCA) appear to play a significant role in causing endothelial damage. However, ANCA are not present in all patients with PAN. In vitro, ANCA can activate neutrophils to adhere more to endothelial cells and to stimulate neutrophils that have been primed with tumor necrosis factor (TNF-Î±) to lyse-cultured endothelial cells. Two types of ANCA are recognized. Perinuclear ANCA (P-ANCA; antimyeloperoxidase) are often found in patients with microscopic polyarteritis or MPA. Cytoplasmic ANCA (C-ANCA; antiproteinase 3) have also been described in patients with polyarteritis nodosa.
Cytokine-induced expression of adhesion molecules (leukocyte function-associated antigen-1 [LFA-1], intercellular adhesion molecule-1 [ICAM-1], and endothelial-leukocyte adhesion molecule-1 [ELAM-1]) allows close contact between polymorphonuclear (PMN) and endothelial cells. The coexistence of cytokine-primed neutrophils, endothelium, and circulating ANCA permit ANCA to initiate a cascade of events leading to vasculitis.
Antiendothelial cell antibodies
Antiendothelial cell antibodies (AECA) are directed against surface endothelial antigens and have been proposed as a pathogenic factor in vasculitis. AECA are not disease specific; they are found both in autoimmune vasculitis and systemic vasculitis. AECA can cooperate in the endothelial injury by increasing endothelial adherence of granulocytes or monocytes through their Fc-gamma-receptor-mediated binding.
Cytokines are potentially involved in the pathogenesis of vasculitis. A marked increase in alpha interferon and interleukin (IL)-2 and a moderate increase in TNF-Î± and IL-1-Î² have been reported in persons with PAN. IL-1 and TNF-a enhance endothelial damage by activating endothelial and PMN cells. Serum basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are angiogenic cytokines that have been shown to be elevated in patients with polyarteritis nodosa.
Polyarteritis nodosa causes transmural necrotizing inflammation of small-sized or medium-sized muscular arteries. Kidneys, heart, liver, GI tract, pancreas, testes, skeletal muscular system, central nervous system (CNS), and skin are involved. The lesions are segmental and may involve partial circumference only. The associated inflammation process may cause weakening of the arterial wall, aneurysmal dilatation, and localized rupture. This is perceived clinically as a nodule, which is also demonstrated by radiology. The area supplied by the involved vessels may slow impaired perfusion, leading to ulceration, infarct, or ischemic atrophy. Occasionally, the lesion may be excessively microscopic and produce no gross changes.
But the pathogenetic mechanism of HBV-related polyarteritis is still unclear. Deposition of immune complexes of HBsAg and HBeAg in blood vessels is thought to be of pathogenic relevance, but the exact mechanism has not been elucidated.
Most evidence suggests that the HBV serum sickness and vasculitis syndromes result from passive deposition of HBV antigen containing CICs(circulating immune complexes) in the vasculature and synovium,followed by complement activation and leukocyte infiltration. The theory is based on the clinical and immunologicals similarities of the HBV syndromes to acute and chronic serum sickness due to foreign antigens in animals and man .As with the HBV serum sickness-like syndrome, acute serumsickness in man is associated with minimal renal manifestations such as mild proteinuria , and acute serum sickness in rabbits is associated with a transient proliferative GN .
HBV-PAN is clinically similar to the vasculitis that can be induced in rabbits and man with repeated injections of foreign antigens, particularly if administered to presensitized individuals.In HBV serum sickness and vasculitis HBsAg probably serves as the foreign antigen. CICs containing HBsAg and anti-HBs antibodies have been detected in most patients with HBV related serum sickness and PAN .Studies in which CICs have not been detected (using hemagglutination, hemagglutination inhibition, and ultra centrifugation) may relate to the sensitivity of the assay .
For example, in idiopathic PAN the Raji cell assay (Test for Circulating Immune Complexes)may correlate better with disease activity as compared to the fluid phase Clq binding assay . Indeed, the presence of CICs as measured by Raji cell assay or by the demonstration of aggregation or"clumping" of HBsAg particles by electron microscopy (EM) has been correlated with disease activity in HBV-PAN.Also of interest is the observation that the infusion of anti-HBs serum into two HBsAg carriers resulted in microscopic hematuria and transient proteinuria, respectively . Systemic complement activation with depressed C3, C4 and total hemolytic complement has also been observed in many but not all patients with HBV serum sickness and HBV-PAN. Finally, clearance of HBsAg from the blood of patients with HBV-PAN, which has only been rarely observed,has been associated with dramatic clinical remission .
The observation that the majority of patients with acute HBV infection have CICs yet extrahepatic manifestations are present in the minority suggests that the content and other characteristics of the CICs may be critical to their pathogenicity. For example, Wands et al examined the contents of CICs in patients with acute hepatitis B with and without arthritis .
Although both groups had CICs containing HBsAg, IgG, andIgM, only patients with arthritis had CICs which also contained complement components (C3, C4, CS) and IgA . CICs from patients with HBV-PAN may also be distinguished from CICs from patients with HBV venulitis on the basis of their dissociability in acid pH (which may reflect antigen-antibody avidity)and relative content of HBsAg .Evidence for a role for HBsAg in HBV serum sickness isfurther provided by studies in which HBsAg has been localizedin synovial vessel endothelium by immunofluorescence (IF) and EM , or has been found in synovial fluid . HBsAg , IgG , and IgM and C3 have also been identified by IF and HBV viral particles by EM in blood vessels of patients with HBV-vasculitis. Immune deposits containg HBsAg have also been demonstrated in glomeruli in patients with HBV-PAN . The observation that IgM is more commonly localized than IgG at blood vessel sites and that HBV-PAN often occurs during the early convalescence of acute hepatitis suggests that IgM rather than IgG immune complexes may be more likely pathogenic in HBV vasculitis.
Musculoskeletal: One half of patients with polyarteritis nodosa have myalgia. The arthritis is an asymmetric, episodic, nondeforming polyarthritis, which predominantly affects the larger joints, especially in the lower extremities, early in the course of disease in 20% of patients. Later in the course of illness, a larger percentage of patients have a more involved polyarticular distribution.
Renal: Rapid renal failure as a consequence of multiple infarcts,renin dependent hypertension, nephritic syndrome, nephrotic syndrome, rapidly progressive glomerulonephritis (RPGN), and ureteral stenosis is a symptom of PAN. PAN seldom leads to renal failure. RPGN is more characteristic of microscopic polyangiitis (MPA).
GI: GI symptoms of polyarteritis nodosa are abdominal pain,digestive tract bleeding, bowel perforation, and malabsorption.
Cardiac and pulmonary: Cardiomegaly, pericarditis, coronary artery involvement leading to ischemia and infarction, pneumonopathy and infiltrates, and pleural effusions (PEs) are symptoms of polyarteritis nodosa.
Reproductive: Orchitis is a symptom in males.
Ocular: Amblyopia and eye pain are symptoms of polyarteritis nodosa.
Small bowel arteritis
Nonspecific, firm, tender subcutaneous nodules without livedo reticularis and/or systemic involvement may be the first sign of polyarteritis nodosa (PAN).
Tender erythematous nodules with central "punched out" ulcerations common in cutaneous polyarteritis nodosa (PAN).
Laboratory tests are nonspecific. Leukocytosis up to 20,000 to 40,000/Î¼L, proteinuria, and microscopic hematuria are the most common abnormalities. Patients may have thrombocytosis, markedly elevated ESR, anemia caused by blood loss or renal failure, hypoalbuminemia, and elevated serum immunoglobulins. AST and ALT are often mildly elevated.
But in hepatitis B-associated PAN, antineutrophil cytoplasmatic antibodies (ANCA) are rarely detected, but immune complexes are often found in patients' sera and endothelia.
Higher titers of HBsAg (89 mg/ml) were found in the serum of patient compared to patients with HBeAg-positive hepatitis B without vasculitis (mean HBsAg: 40 mg/ml~12 mg/ml) . We performed a complete sequence analysis of the HBV genome in order to investigate viral pathogenic factors.
Treatment of hepatitis B virus associated Polyarteritis nodosa
In current therapy, a successful treatment of polyarteritis nodosa with a combination of prednisolone, alpha-interferon and lamivudine is reported. In contrast to most established therapies so far, including long-term administration of immunosuppressive agents like cyclophosphamide, methotrexate, steroids or invasive procedures such as plasma exchange , the current protocol used only a short term immunosuppression combined with an antiviral therapy . The use of immuno suppressive agents is hampered by enhancement of HBV replication and a broad range of side effects. By these protocols HBV seroconversion and improvement of polyarteritis nodosa is achieved in a maximum of half of the cases.
Interferon and nucleoside analogues like vidarabine have been proved bene¬cial in the treatment of HBV-associated PAN, leading to clinical improvement in about 70%-100% of patients and HBeAg seroconversion rates of 50% .With the treatment regimen of alpha-interferon and prednisolone alone,neither reduction of HBV DNA nor improvement of polyarteritis-related symptoms was achieved in patient. Only after the addition of lamivudine and rapid tapering of prednisolone was ef¬cient suppression of HBV replication, complete seroconversion with disappearance of HBsAg and HBeAg and improvement of mononeuritis symptoms obtained .
Evidence in the literature shows that lamivudine alone is effective in active hepatitis and cirrhosis due to HBV. In chronic HBV, viral replication can be suppressed in up to 97% of patients. Seroconversion defined by loss of HBe Ag can be achieved in up to 17% at 1 yr and 27% after 2 yr , and is generally permanent . Control of disease is therefore likely to be achieved in a majority, but on drug withdrawal both clinical and serological relapse may occur .Resistant strains emerge in a proportion of patients after several months of monotherapy. However, the development of resistance may not imply relapse of the disease, and impact may be limited in those who seroconvert, as HBV DNA typically remains suppressed . Combined therapy using IFN alpha and lamivudine may result in seroconversion , but the use of IFN is associated with considerable side-effects and may carry risks for those in whom hepatic decompensation occurs . Severe or rapidly progressive disease may necessitate the use of immunosuppression, which is associated with possible acceleration of viral replication , although concurrent use of lamivudine may prevent this .
Some of the studies show that the effectiveness of HBV associated PAN immunosupressive agents , alpha interferon alpha 2 b(INF a2b) ,and plasma exchange in some amount of patients .
Method of treatment is prednisone was optional and given only in the case of severe or life-threatening manifestations of PAN. When given, every patient took prednisone at a dose of 1 mg/kg/day during the first week of treatment. The prednisone dose was rapidly tapered and steroids were stopped at the end of the second week. In the case of failure of the assigned treatment (lack of clinical improvement or relapse), prednisone was given againat a dose of 1 mg/kg/day.
Interferon-alpha 2b (INFÎ±2b)
INFÎ±2b was started just after the patient's inclusion in thestudy. It was initiated at a dose of 3 millionunits, three times a week. The treatment duration depens on the results of HBVreplication tests. In the case of seroconversion within the weeks following INFa2b, the antiviral treatment was stopped. If Hbe antigenaemia remained positive, INFa2b was administered for one year and additional treatments could be given later on, depending on the patient's liver function status.
Patient had plasma exchanges, which were started just after the patient's inclusion in the study. Each patient had 9 to 12 plasma exchanges during the first three weeks of treatment with INFa2b. During this period, the number of plasma exchanges depended on vascular access and the level of clotting factors before plasma exchanges. After this period, plasma exchanges were performed two or three times a week, depending on the clinical results observed, and then stopped. The amount of plasma scheduled to be exchanged during each session was 60 ml/kg of body weight. The replacement fluid consisted of 500 ml of fluid gelatin and 4% albumin.
The result may show that HBeAg/anti-HbeAb seroconversion was observed in patients (66.6%) and HBsAg/anti-HBsAb seroconversion occurred in (50%). The results lead us to think that antiviral therapy will have a role of play in the treatment of virus induced vascular disease and HBV-related PAN. In HBV-related PAN, the association of INFa2b and plasma exchanges is effective, an facilitates recovery from the vasculitis and HBeAg/anti-HBeAb seroconversion.
What is plasma exchange?
Plasma exchange is a procedure in which your blood is separated into its different parts: red cells, white cells, platelets and plasma. The plasma is then removed from the blood and a plasma substitute returned in its place.
Why plasma exchange may be done?
abnormal plasma cells may make large amounts of a protein called immunoglobulin. If the levels of immunoglobulin in the blood become very high, the blood can become thicker than normal, causing symptoms such as headaches, blurred vision and tiredness. This is sometimes called hyperviscosity syndrome.
Plasma exchange can reduce the amount of abnormal protein in the blood and so improve symptoms. It does not stop the protein being produced, however, and so it is often necessary to have other treatment, such as, to reduce the production of the protein.
How plasma exchange is done?
Plasma exchange is carried out using a machine called a cell separator, which can separate blood cells and plasma. A needle is usually inserted into a vein in each arm. Blood is taken from a vein in one of your arms and circulated through the cell separator. This separates off the plasma and the rest of your blood is returned into your vein through the needle in your other arm.
To replace the plasma that is removed a plasma substitute is given with the returned blood cells. As blood is being taken from you and returned to you at the same rate only a small amount of blood is outside your body at any time.
Each plasma exchange takes about two hours. The rate of plasma exchange is decided according to your height, weight and the thickness (viscosity) of your blood. The number of plasma exchanges that you need will depend on the amount of protein in your blood, your symptoms and your response to other treatments.
Acute hepatitis B and arthritis
The first reported association of acute viral hepatitis with arthritis was that of Sir Robert Graves in an 1843. Since that time, a number of reports have described discomfort in joints of a transient nature preceding the icteric phase of hepatitis occurring in anywhere from 1 percent to 40 percent of cases.Clinically, the syndrome resembles one-shot serum sickness syndrome. The symptoms are generally abrupt in onset and consist of low-grade fever, a symmetrical polyarthritis which may be additive or migratory in pattern, morning stiffness and other constitutional symptoms. The joints most commonly involved are the knees and small joints of the hands. For some reason, the feet are usually spared, but almost any peripheral joint may be involved, with either arthralgia or actual arthritis.In more than 50 percent of cases, a skin rash may accompany or follow shortly after the onset of manifestations in joints. Although usually described as urticarial, this rash may also be erythematous, maculopapular or petechial in nature.
This syndrome may last from several days to several months; in one large series the mean duration was 20 days.Only about 40 percent of the patients ever become jaundiced, in keeping with the accepted incidence of anicteric hepatitis
B in general. If jaundice does occur, it may be present initially; more frequently, it develops two to four weeks after the onset of arthritis.The symptoms usually abate with the onset of jaundice or respond quite well to salicylate therapy alone.
It has been observed that when the episode of arthritis is longer in duration, the picture can much resemble rheumatoid arthritis. On occasion, a tentative diagnosis of rheumatoid arthritis has been made until either clinical jaundice or significantly abnormal liver test results have made the correct diagnosis apparent.
Typically, the arthritis and rash resolve at about the time that jaundice develops.
In addition, the patients almost always manifest the more nonspecific symptoms of early viral hepatitis such as malaise, sore throat, anorexia and nausea; but in one large series, it was most often the joint discomfort and rash that motivated the
patients to seek medical attention. There is nothing distinctive about the routine
laboratory studies except for the abnormal results of liver enzyme tests.
HbsAg found in about 70 % of patients with this syndrome and anti HbsAg was fount in the about 30 % of patients. The low serum complement levels, the presence of HBsAg and the lack of detectable antibody during this syndrome are in keeping with the expected pattern of an acute illness that is very like serum sickness.
Patients with viral hepatitis who do not have joint or skin symptoms do have normal or increased complement levels. This inverse correlation of antigen and complement suggests consumption of the latter by immune complexes containing HBsAg; it also suggests that their deposition in synovium might be responsible for the articular symptoms. Earlier work had shown that HbsAg does induce, in man, formation of an antibody that can form an immune complex and fix complement. Further evidence to support an immune complex pathogenesis for this syndrome includes the finding of HBsAg by complement fixation techniques in serum and synovial fluid specimens simultaneously obtained in the acute phase as well as cryoprecipitates containing immune complexes (that is, HBsAg, IgG, IgM, IgA and complement components C3, C4 and C5). Interestingly, the cryoprecipitates from patients with hepatitis without arthritis contained only HBsAg,IgG and IgM and were present in lesser concentration than in patients with hepatitis and arthritis.As antigen titers decreased and became undetectable during convalescence, free antibody became detectable in the serum. Light microscopy examination of a synovial biopsy specimen from a patient with the acute hepatitis B arthritis syndrome showed areas of slight cellular proliferation, vascular congestion and occasional lymphocytes.
Chronic active hepatitis
Joint discomfort and occasional rash have long been mentioned in association with chronic active hepatitis, both with what had been termed lupoid
hepatitis and in cases associated with chronic or recurrent hepatitis B antigenemia. In chronic active hepatitis, the joint complaints consist mainly of arthralgias of a fleeting nature and perhaps for this reason less investigation into the nature of this syndrome has been done. A recent report describes a case of asymmetrical polyarthritis with erythematous skin lesions in a patient with biopsy proven, HBsAg positive chronic active hepatitis. No antiHBsAg was found in the serum, as expected, and serum total hemolytic complement was very low. Examination of needle biopsy specimens of involved synovium revealed changes similar to those in the patients with acute hepatitis.
Essential mixed cryoglobulinemia
Finally, and most recently, an association between essential mixed cryoglobulinemia and the HBsAg has been reported. This syndrome was first reported in 1966 and clinically presents with nonthrombocytopenic dependent purpura upon exposure to cold,diffuse arthralgias,generalized weakness, hepatosplenomegaly, and occasionally neuropathy and gangrene. In about 50 percent of patients, kidney involvement leads to renal failure in a rather short time. Histologically, an immune complex vasculitis and glomerulonephritis are present,
with evidence of IgG, IgM and complement deposition at the sites of tissue damage. The mixed cryoglobulins isolated from the blood in these patients also consist of IgG and IgM, and occasionally IgA and complement components. The
IgM may be polyclonal or monoclonal and has rheumatoid factor (antiglobulin) activity. The renal disease, when present, is the usual cause of death. Presence of cryoproteins has been reported in patients who have positive HBsAg test results30 and in others who have the previously mentioned syndromes. However, in essential cryoglobulinemia the amount of cryoprotein present is usually greater (from 1 mg per ml up to 5 mg perml), and symptoms are precipitated upon exposure to cold.
Within the past year, Levo and co-workers have reported that 60 percent of
patients who previously would have been classified as having the "purpura arthralgia weakness syndrome" have been shown to have evidence of hepatitis B infection. Of the serum specimens from their patients,only 12 percent contained free HBsAg, but 48 percent had free antibody. Examination of the cryoproteins themselves showed that 74 percent contained either antigen or antibody. Examination by electron microscopy of the cryoprecipitates showed structures resembling the Dane particle of hepatitis B virus. Furthermore,liver involvement in essential mixed cryoglobulinemia was clinically or biochemically shown to be present in 84 percent of their patients. Though only a few had overt liver disease, studies of biopsy specimens from a number of patients showed a varying spectrum from minimal change to chronic active hepatitis and cirrhosis. Thus, we now have evidence that in many patients,essential mixed cryoglobulinemia is not essential at all but represents yet another syndrome in the spectrum of manifestations of hepatitis B virus infection in man.
HBV-MGN was first reported by Combes et al in 1971 who described a 53-year-old man who became a chronic HbsAg carrier following an episode of symptomatic post-transfusion hepatitis. One year later he presented with nephrotic syndrome due to MGN in which HBsAg could be localized in the glomerular capillary wall by immuonfluourscense staining . The association of the chronic "carrier" state of HBV with membranous nephropathy is now well established, particularly in children, where the frequency of the HBsAg carrier state in MGN correlates with the underlying prevalence of HBsAg in the general population. In general, the frequency of HBsAg carriage in adult patients with MGN is still significant but of a smaller magnitude.