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REVIEW ARTICLE Table of Contents   
Year : 2006  |  Volume : 3  |  Issue : 1  |  Page : 128-154
Extrahepatic manifestations of chronic hepatitis B


1 Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angels, CA, USA
2 Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angels, CA, USA

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   Abstract 

Hepatitis B virus (HBV) infection and its complications are global health problems. Approximately 400 million people are chronic HBV carriers worldwide. The spectrum of chronic HBV infection ranges from asymptomatic hepatitis B surface antigen (HBsAg) carrier state to chronic hepatitis with progression to cirrhosis and end-stage liver disease. It is estimated that 15% to 40% of people with chronic HBV will progress to cirrhosis. Several extrahepatic syndromes are associated with chronic HBV infection. These syndromes contribute significantly to morbidity and mortality. The mechanism of extrahepatic syndromes seen with chronic viral hepatitis appears to be immune-mediated. including deposition of circulating immune complexes, induction of local immune complex formation by viral antigens, reaction with tissue antigens by viral-induced autoantibodies, or a direct viral reaction to extrahepatic tissue sites. Polyarteritis nodosa (PAN) is a rare, but serious, systemic complication of chronic HBV infection affecting the small- and medium-sized vessels. PAN ultimately involves multiple organ systems, some with devastating consequences, though the hepatic manifestations are often more mild. HBV-associated glomerulonephritis (GN) occurs mainly in children, predominantly males, in HBV endemic areas of the world. In children, GN is usually self-limited with only rare progression to renal failure. In adults, course of GN may be more relentless, progressing slowly to renal failure. A serum-sickness like "arthritis-dermatitis" prodrome is also seen in some patients acquiring HBV infection. The joint and skin manifestations are varied, but the syndrome spontaneously resolves after the onset of clinical hepatitis without significant sequelae. Occasionally, the arthritis following the acute prodromal infection may persist; however, joint destruction is rare. The association between HBV and mixed essential cryoglobulinemia remains controversial. Finally, skin manifestations of HBV infection typically present as palpable purpura. Though papular acrodermatitis of childhood has been reported to be caused by chronic HBV, this association remains controversial.

How to cite this article:
Shim M, Han SHB. Extrahepatic manifestations of chronic hepatitis B. Hep B Annual 2006;3:128-54

How to cite this URL:
Shim M, Han SHB. Extrahepatic manifestations of chronic hepatitis B. Hep B Annual [serial online] 2006 [cited 2019 Sep 22];3:128-54. Available from: http://www.hepatitisbannual.org/text.asp?2006/3/1/128/32776



   Introduction Top


Hepatitis B virus (HBV) infection and its complications are global health problems. Approximately 400 million people are chronic HBV carriers worldwide.[1] The spectrum of chronic HBV infection ranges from asymptomatic hepatitis B surface antigen (HBsAg) carrier state to chronic hepatitis with progression to cirrhosis and end-stage liver disease.[2],[3] It is estimated that 15-40% of people with chronic HBV will progress to cirrhosis.[4]

In endemic regions of the world such as Southeast Asia, Africa and the Pacific Islands, vertical transmission from infected mothers and perinatal transmission from infected family members are the predominant routes of HBV passage. In less endemic Western countries, HBV transmission occurs as a consequence of high-risk sexual practices or injection drug use.

Several extrahepatic syndromes are associated with chronic HBV infection [Table - 1]. These syndromes contribute significantly to morbidity and mortality.[5] The mechanism of extrahepatic syndromes seen with chronic viral hepatitis appears to be immune-mediated.[5] Indeed, patients with chronic viral hepatitis commonly have immunologic manifestations including circulating autoantibodies and concurrent autoimmune disorders.[6] Other possible mechanisms, which will be discussed subsequently, include deposition of circulating immune complexes (IC's), induction of local IC formation by viral antigens, reaction with tissue antigens by viral-induced autoantibodies or a direct viral reaction to extrahepatic tissue sites.[5]


   Polyarteritis nodosa Top


Polyarteritis nodosa (PAN) with necrotizing vasculitis is one of the more serious extrahepatic syndromes associated with chronic HBV. This association was first recognized in 1970 by Gocke and Trepo.[7],[8] PAN is considered a rare complication of chronic HBV infection, occurring in only about 1-5% of patients with chronic HBV.[9],[10] On the other hand, positivity for serum HBsAg is observed in 40-50% of patients with PAN[11],[12] and in some vasculitis series, the reported incidence of HBV infection in PAN patients ranges from 30 to 70%.[5],[13] Indeed, in one European study, the incidence of chronic HBV infection in patients with PAN was found to be higher than initially expected. In this study, Marcellin et al. reported that among 28 patients with PAN, 12 patients had HBsAg positivity and seven patients had positivity for hepatitis B core antibody (HBcAB) and/or hepatitis B surface antibody (HBsAb).[14] Since then, however, the frequency of new cases of PAN related to HBV has declined to 7.3% owing to the increased use of HBV vaccines as preventative measure against HBV spread.[12] Interestingly, HBV's association with PAN has been reported predominantly in North America and Europe, where HBV is typically acquired later in life. In Asia, where HBV is acquired perinatally, the association of PAN has not been observed.[15]

From a clinical standpoint, the presentation of HBV-related PAN is similar to the typical form of PAN.[16] The initial illness presents with systemic hypertension, eosinophilia, abdominal pain, rash, polyarthritis, polyarthralgias and weight loss, eventually progressing to involve the kidneys, gastrointestinal tract, skin and nervous system (central and peripheral).[13],[17],[18],[19] In 1976, Duffy and Sergent reported the specific clinical findings seen in a combined cohort of 19 patients with HBV-related PAN.[17],[18] These findings are detailed in [Table - 2], but in general, included fever, anemia, leukocytosis, liver test abnormalities, polyarthritis, nephrotic syndrome, congestive heart failure, bowel infarction, nervous system involvement and low serum complement levels. Indeed, seven of the 19 patients ultimately died of their systemic vasculitis. Guillevin et al.[12] noted that the clinical manifestations of HBV-related PAN were similar to typical PAN except for the following notable exceptions: gastrointestinal complications of perforation and bleeding seen in 46.3%, malignant hypertension seen in 29.6% and renal infarction and orchiepididymitis seen in 26%. Hepatic manifestations are varied, ranging from mild to moderate elevations of serum aminotransferase levels and, rarely, cholestasis.[16] Interestingly, however, histological liver disease ranged from mild periportal inflammation to established cirrhosis as reported by Sergent and Duffy.[17],[18]

The course of PAN is often protracted, ultimately involving multiple organ systems.[20] Gastrointestinal symptoms are prominent findings in almost 50% of cases and include non-specific pain and diarrhea. Dermatologic manifestations in PAN occur 10-15% of the time[20] and include the triad of painful subcutaneous nodules (usually seen along the arteries of the lower extremities), livedo reticularis and ulceration. Acral gangrene can also be seen. The clinical signs and symptoms may occur prior to, coincident with or following the onset of the liver disease.[13],[17],[21] Patients may experience a prodrome lasting several weeks in duration, but in approximately 50%, the onset of PAN is abrupt.[21]

The pathogenesis of HBV-related PAN has been attributed to circulating IC's composed of HBsAg/Ab and complement, but this remains controversial.[19] In HBV-related PAN, unlike typical PAN, serum antineutrophilic cytoplasmic antibodies (ANCA) are rarely detected.[19],[22] The immunological process responsible for PAN commonly occurs within 6 months of HBV infection.[16] HBV IC's have been found in leukocytoclastic vasculitis of smaller vessels in this disease.[23],[24] Indeed, Fye et al. reported that circulating IC levels were proportional to disease activity, strongly implicating circulating IC's in the pathogenesis of HBV-related PAN.[25] However, other investigators have found that during active vasculitis, serum complement levels are low and vascular deposits of HBsAg, immunoglobulins and complement are seen in the laminae of affected arteries,[7],[26] thus implicating complement components. When inactive, viral and host complement components are not detectable.[11],[26] This association between disease activity and complement level has been well-correlated such that some authors have suggested monitoring of complement levels as a helpful guide to disease activity and effectiveness of therapy.[21] Finally, electron microscopy has revealed HBsAg precipitates around post-capillary venules[23],[24] and some investigators have suggested that changes in HBsAg and anti-HBs titers correlate better with disease activity,[27] reaffirming the controversial nature of this disease.

To confuse the picture further, more recent compelling literature has implicated hepatitis Be antigen (HBeAg) in the pathogenesis of the disease. Using immunostaining and ultrastructural techniques, Trepo et al. noted findings indicating that HBeAg is more likely to be the responsible antigen in HBV-related PAN.[16] Most notably, HBeAg in its free form is 19 kDA in size, in contrast to HBsAg, which is 3 million kDA. Studies of experimental serum sickness and glomerulonephritis have shown that only IC's of 1 million kDA or less are capable of crossing microscopic barriers to cause lesions. Indeed, some investigators feel that PAN disease activity is linked to HBV replication and NOT HBs antigenemia per se , as some patients cured of PAN for many years remained HBsAg carriers after HBeAg seroconversion and HBsAg/Ab complexes were never observed to be associated with PAN reactivation.[16] Additionally, the overwhelming number of HBV-related PAN cases has been associated with wild-type HBV and HBe antigenemia. However, this latter observation may be refuted somewhat based on two isolated case reports of HBeAg-negative "precore" mutant HBV-associated PAN.[28],[29] In one case, the authors reported success with combination therapy (prednisolone pulse, plasma exchanges and interferon-a) in inducing HBV DNA undetectability with resolution of PAN symptoms.[28] In the other case, the patient experienced a severe relapse of PAN following initial treatment with corticosteroids and interferon-a.[29]

Histologically, the vasculitis is characterized by fibrinoid necrosis and perivascular inflammation of small- and medium-sized vessels.[5],[13] In the acute phase, polymorphonuclear leukocytes (PMN's) infiltrate the vessel wall. Chronically, a mononuclear infiltrate predominates with possible progression to vessel occlusion, thrombosis, ischemia and ultimately necrosis.[20] Angiographically, the findings include arterial microaneurysms, stenosis and occlusion (5;30). Indeed, renal angiography in most patients with PAN will show virtually pathognomonic microaneurysms.[30] As a result of severe vessel involvement, visceral infarction is common, occurring in the gastric antrum, small intestine, colon, kidneys, gallbladder, liver, spleen, pancreas, brain, heart, testes and prostate. Pancreatitis and cholecystitis may result. Visceral infarction may lead to hemorrhage and gastrointestinal perforation in 16%, which can be catastrophic events. Computer tomography (CT) scans can demonstrate visceral infarction in the liver, kidneys, spleen and brain.[30] On abdominal plain films, gastrointestinal infarction may appear as 'thumbprinting,' and areas of resolved ulceration or perforation may persist as areas of stenosis.[30]

Untreated, the prognosis of HBV-related PAN is poor with 30-50% dying as a consequence of vasculitis.[5] In one series, three of nine patients died of vasculitis within 6-8 months of disease onset.[17] The six surviving patients all had significant residual complications of their vasculitis such as malignant hypertension, neuropathy and azotemia.

The conventional treatment of typical PAN, consisting of long-term corticosteroid therapy, immunosuppressive medications and plasma exchange therapy, can have deleterious effects on HBV-related PAN due to their negative impact on underlying liver disease and HBV replication.[31] Conventional treatment was often effective in the short-term, but long-term outcome was plagued by relapses and complications of chronic liver disease related to viral persistence.[16],[32],[33] Indeed, in two studies, patients recovering from PAN still progressed to die of liver-related complications.[10],[34] However, given that conventional treatment demonstrated short-term, though inconsistent, benefits,[10],[12],[13] some investigators suggested empirical corticosteroid or immunosuppressive therapy and cytotoxic agent use during the active disease, after which, therapy can be withdrawn without apparent recurrence of PAN nor exacerbation of underlying liver disease.[21] On the other hand, there has been a reported risk of exacerbation of viral and liver disease by withdrawl of corticosteroids and immunosuppressive therapy.[35],[36]

Subsequently, attention turned to antiviral treatment of underlying chronic HBV in the hopes of alleviating the symptoms of PAN. Two individual case reports demonstrated benefit with the use of interferon-a monotherapy in patients with HBV-related PAN. Simsek described successful treatment in a 43-year old gentleman administered interferon-α-2a 4.5 million units daily for 6 months.[37] Therapy resulted in loss of HBV DNA, though HBeAg and HBsAg remained. His PAN symptoms improved markedly. In another case report, Avsar et al. described successful treatment of PAN in a patient with chronic HBV, utilizing interferon-a 5 million units daily for 24 weeks.[38] In this case, therapy resulted in HBeAg and HBsAg seroconversion with resolution of PAN symptoms.

The combination of antiviral therapy (interferon-α) and plasma exchanges has proven effective.[39] This approach is favored by some investigators who believe plasma exchanges are needed to rapidly clear IC's to minimize life-threatening complications of PAN while undergoing antiviral therapy.[16] Using this combination in six patients, Guillevin et al. reported successful HBeAg seroconversion in four patients and HBsAg seroconversion in three patients.[40] Following therapy, relapse rates have been reported to be rare.[12] Furthermore, prolonged antiviral therapy is recommended (at least 6-12 months) until clearance of HBV DNA and HBeAg seroconversion has occurred.[16] Combination therapy with another antiviral agent, Vidarabine or interferon-α in conjunction with plasma exchanges has shown efficacy in one study of 41 patients with HBV-related PAN.[12] In this long-term study, 51% achieved HBeAg seroconversion and an impressive 24% achieved HBsAg seroconversion. Perhaps more importantly, 80% remained PAN symptom-free at long-term follow-up.

These same investigators also reported their cumulative success in 80 patients with triple combination therapy using a short-course of corticosteroids followed by antiviral therapy with vidarabine, interferon-α or lamivudine and plasma exchanges in HBV-related PAN.[41] After a mean follow up of 69 months, only 5% had PAN relapse and 50% underwent HBeAg seroconversion. Gupta et al. reported successful therapy of PAN associated with acute HBV with triple therapy consisting of plasmapharesis, lamivudine and a short taper of corticosteroids.[42] In this patient, there was resolution of HBV and improvement in the PAN symptoms. Another study in ten patients reported clinical recovery from PAN in nine patients and HBeAg seroconversion in six after treatment with prednisone for two weeks followed by lamivudine and plasma exchange.[43]

Combination therapy with two antiviral agents has shown promise. Kruger et al. reported that combination therapy with interferon-a and famciclovir significantly reduced HBV viral replication with marked improvement in symptomatology within 4 weeks of initiating therapy.[44] In long-term follow-up on famciclovir therapy, this patient has maintained low levels of HBV DNA with HBeAg seroconversion and has remained completely asymptomatic of PAN without emergence of any clinically significant famciclovir-resistant mutants. Combination therapy with interferon-a and lamivudine has also been used successfully.[45],[46] Erhadt et al. reported their results of triple therapy adding lamivudine to interferon-a after an initial course of fast tapering of prednisolone.[46] HBV DNA levels became undetectable within one month and HBeAg seroconversion occurred after 6 months, followed by HBsAg seroconversion two months later. In their patient, no relapse of PAN or HBV has occurred in a 9-month follow-up and there was no emergence of the lamivudine-resistant (YMDD) mutant. Finally, Deleaval et al. reported successful treatment of PAN and rapid HBsAg seroconversion using a combination of interferon-a, lamivudine, 5 weeks of plasma exchange and one month of steroids. HBeAg seroconversion occurred after only two weeks of lamivudine added to interferon and HBsAg seroconversion occurred at four weeks.[47]


   Glomerulonephritis Top


The association between chronic HBV and glomerular disease dates back to the 1970s.[48] This extrahepatic syndrome occurs mainly in children, predominantly males, in HBV endemic areas of the world and is only occasionally reported in the United States.[5] In these children, liver tests are frequently normal and 60% show spontaneous complete remission in follow-up.[15]

The actual prevalence of HBV-related glomerulonephropathy (GN) is difficult to determine, because although many patients with renal disease have HBsAg, only a minute proportion have demonstrable HBV antigens in the kidney. On the other hand, IC deposits in patients with viral hepatitis have been detected in the kidneys in the absence of renal disease.[5] Additionally, the frequency of association between HBV and glomerulonephritis is controversial owing to wide variation in reported incidence.[13] In one study, HBsAg has been detected in 35% of renal biopsies in Polish children with glomerulonephritis and nephrotic syndrome,[49] but lower frequencies have been reported in Europe, Japan and in only 1% in the United States.[50]

The most frequent presentation of HBV-related GN is nephrotic syndrome.[5],[21] A history of prior liver disease is uncommon, though liver biopsies always show varying degrees of liver disease.[5] As previously stated, the disease is usually self-limited in several months to years (85% by 2 years, 95% by 5-7 years), especially in children with membranous glomerulonephropathy (MGN). This resolution is often associated with HBeAg seroconversion and there is only rare progression to renal failure.[5]

In adults, the natural disease course may be more relentless, slowly progressing to renal failure. Lai et al. studied 21 adult patients with HBV-related membranous nephropathy followed for 60 months.[51] All patients acquired HBV perinatally and had HBeAg in renal biopsy specimens. In 16 untreated patients, proteinuria persisted with 29% progressing to renal failure and 10% eventually requiring hemodialysis. In these adult patients, there is usually a history of acute hepatitis several months to years before the onset of kidney disease.[15] Additionally, liver tests are usually abnormal with chronic liver disease on liver biopsy.[15]

Similar to PAN, the pathogenesis of HBV-related GN is believed to be due to circulating IC's. Circulating IC's of HBsAg and anti-HBs, as well as stainable and elutable HBsAg and anti-HBs have been demonstrated in the glomerular basement membrane of patients with HBV-related GN.[48],[49],[52],[53] In fact, all three major HBV antigens (HBsAg, HBeAg and HBcAg) have been localized in glomerular capillary wall or mesangium.[26],[54],[55],[56],[57] HBeAg-anti-HBe IC's have been implicated in the pathogenesis of MGN disease, owing to the small size of HBeAg to penetrate the basement membrane; whereas, HBsAg-anti-HBs IC's have been implicated for mesangial proliferative GN (MesPGN) and membranoproliferative GN (MPGN) due to its larger size.[48],[58] However, the role of HBeAg in MGN is still controversial, as several studies have noted remission of proteinuria without HBeAg seroconversion or persisting proteinuria despite HBeAg seroconversion.[58],[59],[60],[61],[62] Additionally, Morzycka et al. noted in their autopsy study of HBV infected patients that kidney lesions (MGN and MPGN) were frequent, but only 15-20% had clinical evidence of renal disease and concluded that the renal lesions do not necessarily correlate with renal disease in chronic HBV infection.[63] Indeed, L'Abbate et al. even challenged the idea that HBV-related GN exists, as they found that fluoresceinated anti-HBs cross-reacted with rheumatoid factor in the glomeruli, resulting in a false-positive determination.[64]

The diagnosis of HBV-related GN is established by serological HBV infection and the presence on kidney biopsy of IC glomerulonephritis with glomerular deposits containing one or more HBV-related antigens by immunocytochemical staining.[5] Most patients will also have activation of the complement cascade, resulting in low serum C3 and C4 levels.[5] Several types of GN exist, but MGN and MPGN are the two most common types.[13],[65],[66] MGN is the most common type in children and MPGN is more common in adults.[65],[66]

Membranoproliferative GN (MPGN)

Histologically, MPGN is associated with mesangial and capillary wall deposits of HBsAg. Although the pathogenesis is not fully understood, it likely involves glomerular deposition of circulating IC containing HBV antigens. This is supported by the demonstration of circulating HBsAg-anti-HBs IC's, HBsAg, immunoglobulins, complement components and visualization of dense deposits bearing HBsAg immunoreactivity in a thickened glomerular basement membrane in these patients.[48],[50] Additionally, HBeAg and HBcAg have also been found in glomeruli.[57],[67] With persistent viral infection, the heightened immune response favors formation of circulating IC's, with ultimate deposition into extrahepatic sites.[5]

Mesangial Proliferative (IgA) GN (MesPGN)

The role of HBV in MesPGN is controversial. Chung et al. found no association between remission of proteinuria in their two treated patients with MesPGN and HBeAg seroconversion.[58] On the other hand, Wang et al. described 50 patients with MesPGN and hepatitis B antigenemia and/or hepatitis B virus antigens detected by immunohistochemistry in renal biopsies. 96% of the patients had HBsAg and/or HBcAg detected in renal tissue and 72% had HBV DNA detected in glomeruli.[68]

Membranous GN (MGN)

Histologically, MGN is associated with capillary wall deposits of HBeAg. In contrast to MPGN, the pathogenesis of MGN is felt to be due to IC formation in situ secondary to induction of autoantibodies to intrinsic glomerular antigens.

Treatment with corticosteroids or immunosuppressive medications remains controversial, as patients receiving corticosteroids have had no benefit or only transient, incomplete benefit.[5] One report claims worsening of morbidity and mortality with corticosteroids or immunosuppressives.[69] Indeed, given the high spontaneous remission rate in children with HBV-related MGN, use of corticosteroids or immunosuppressives is not recommended.[5]

Antiviral therapy with interferon-a may hold promise. In fact, MGN may respond more favorably to interferon-a therapy than MPGN.[5] Early case reports showed improvement in renal disease with clearance of HBV replicative markers after interferon-a therapy,[70],[71],[72],[73] though in two cases, improvement in renal disease occurred in the absence of viral antigen seroconversion.[73],[74]

Lisker-Melman et al. reported good results with a 4-months course of interferon-α therapy in patients with chronic HBV-related GN and nephrotic syndrome.[75] Four of five patients treated who loss serum markers of viral replication were associated with marked improvement in proteinuria.

Conjeevaram et al. reported a long-term follow-up of chronic HBV-related GN patients treated with interferon-α at the National Institutes of Health (NIH).[76] In eight of 15 sustained responders (defined as loss of HBeAg and HBV DNA), seven patients showed marked improvement in proteinuria. The nonresponders showed progressive renal disease. Eight responders had MGN, whereas, four of seven nonresponders had MPGN.

Chung et al. treated eight male adults with HBV-related GN with interferon-α 3 million units thrice weekly for 6 months.[58] Four patients had MPGN, two patients had MesPGN and two patients had MGN. In three (2 MPGN and 1 MesPGN) of seven patients completing the full course, a sustained HBeAg seroconversion occurred. None of the MPGN patients showed improvement in proteinuria. In both MesPGN patients, proteinuria improved. In the two patients with MGN, proteinuria persisted.

Lin et al. reported favorable results in 20 Asian children with HBV-related MGN treated with interferon-α 5 million units thrice weekly for 12 months compared to 20 untreated controls.[77] Although only 40% of treated patients developed HBeAg seroconversion, all 20 resolved proteinuria. In comparison, 0% seroconverted in the untreated controls, though 50% developed spontaneous improvement in proteinuria. In contrast, Lai et al. reported poor results in five adults with HBV-related MGN treated with interferon-a.[51] Only one of five patients developed HBeAg seroconversion. Additionally, in long-term follow-up of 16 patients who were not treated with interferon-a, proteinuria persisted in all with 29% progressing to renal failure and 10% eventually requiring hemodialysis.

Two recent case reports and one case series have demonstrated the efficacy of lamivudine treatment for MGN with resolution of proteinuria and nephrotic syndrome.[78],[79],[80] In the case series, 10 patients with chronic hepatitis B and MGN were treated with lamivudine and experienced significant reduction in proteinuria, normalization of ALT levels and hepatitis B DNA suppression compared to 12 historical controls who did not receive lamivudine. Cumulative 3-year survival free from end stage renal disease was 100% in the lamivudine treated group and 58% in the untreated group.[80]


   Serum sickness -like syndrome (prodrome) Top


The serum sickness-like prodromal phase occurs 1-6 weeks prior to clinical hepatitis and is very common, occurring in 10-30% of those acquiring acute HBV.[13],[17],[18],[20],[21],[81],[82] This syndrome has also been termed the 'arthritis-dermatitis' prodrome in regards to the predominant symptoms. Clinically, the syndrome is characterized by polyarthralgias or arthritis with joint edema and swelling indistinguishable from acute rheumatoid arthritis. Indeed, rheumatoid arthritis is often mistakenly diagnosed until clinical jaundice develops. The arthritis is generalized and symmetrical, involving the small joints of the hands and feet, but can also be asymmetric and monoarticular, involving a few large joints including the knees, wrists and ankles. There can also be spinal involvement.[16] Frequently, the arthritis is extremely painful, disproportionate to the swelling. Similar to rheumatoid arthritis, there may be morning stiffness with a 'gel' phenomenon. Synovial fluid analysis is variable. PMN's can range from 465 to 90,000/cu mm.[18] The fluid may even be non-inflammatory.[83] During the acute phase, synovial fluid shows HBsAg and reduced complement levels.[83],[84],[85] Histologically, one sees cellular proliferation, vascular congestion and occasional lymphocytes.[86] However, the joint lesions are nondestructive and permanent damage does not occur.

Skin manifestations are variable, ranging from discreet eruptions to rash and occur in more than 50% accompanying or shortly following the joint manifestations.[27] The lesions can be maculopapular, purpuric or petechial. Other manifestations include palpable purpura, Henoch-Schonlein-type purpura, erythema multiforme, toxic erythema and lichenoid dermatitis.[20],[87] Biopies of these lesions reveal a cutaneous vasculitis with immunoglobulins, complement and HBsAg in blood vessel walls.[87]

An urticarial lesion can be intermittent or may be the only presenting sign.[16],[23] Often, this lesion is associated with hypocomplementemia.[87],[88],[89],[90],[91] The histopathology of the lesion shows leukotaxic urticaria with a perivascular infiltrate of PMN's, leukocytoclastic vasculitis, endothelial and dermal edema, fibrinoid occlusion and hemorrhage.[20],[87] IC's may mediate their action to produce lesions via production of the anaphylatoxins C3a and C5a to manifest urticaria.[20]

Proteinuria or hematuria from renal involvement is much less frequent,[17],[20] though direct immunofluorescence of the kidney has demonstrated IC's.[48] Fever may be present. Occasionally, angioedema is seen, occurring in about 4%.[20]

Immunologically, the serum sickness-like prodrome is similar to acute serum sickness or 'one-shot serum sickness.' HBsAg-anti-HBs IC's are felt to be responsible. Clinical symptoms occur during the period of relative antigen excess and soluble IC's, but as increasing antibody titers form, IC's become less soluble and are cleared more readily with consequent decrease in symptoms.[84] Additionally, the active phase is characterized by depressed complement levels, which returns to normal with recovery.[84] Interestingly, though a high percentage of patients have circulating IC's during this syndrome, only a minority develop clinical symptoms; therefore, the serum sickness analogy may not be perfect and other undetermined host or viral factors must be at play.

The serum sickness-like syndrome typically lasts several days to several months with a mean duration of 20 days in one large series.[18],[27] It resolves abruptly at the onset of clinical hepatitis without recurrence.[16]


   Essential mixed cryoglobulinemia Top


The association of essential mixed cryoglobulinemia (EMC) with chronic HBV was described by Levo et al. , who found evidence of HBV infection in the cryoproteins of 74% of their patients with EMC in addition to clinical and biochemical evidence of liver involvement in 84%.[92],[93] Liver biopsies in their patients also demonstrated a spectrum of disease ranging from minimal change to cirrhosis. However, this association between chronic HBV and EMC was deeply controversial,[94],[95] based on a later study by Popp et al. who found only two of 12 of their patients with EMC had evidence of liver disease.[95] Subsequently, Lunel et al. reported a 15% incidence of mixed cryoglobulinemia in 40 patients with chronic HBV.[96] HBV DNA was found in the cryoprecipitates of these patients, though the titers were low and the patients were asymptomatic. EMC is felt to be an immune-mediated disorder caused by IC's that precipitate at lower temperatures.[20] The mixed cryoglobulins isolated from the blood consists of IgG, IgM, occasional IgA and complement components.[27] Serum complement levels are frequently depressed.[92]

The clinical syndrome is characterized by a triad of recurrent arthritis, purpura and weakness (hence the term 'purpura, arthralgia, weakness syndrome'), followed by eventual glomerulonephritis, pulmonary disease and generalized vasculitis.[20],[21],[23] Without nephritis, the clinical course is protracted, but benign. With nephritis (in about 50%), the clinical course is rapidly deteriorating with death usually due to renal disease.[27] Palpable purpura of the lower extremities can also be associated with erythrocyanosis and Raynaud's phenomena.[92]

In general, treatment of the underlying hepatitis B leads to clinical and serologic resolution of ECM. One case report demonstrated successful use of interferon-a[97] while another reported successful use of lamivudine after failure of prednisone.[98]


   Dermatologic manifestations Top


Skin rashes in chronic HBV are more likely to have palpable purpura, which histologically is a neutrophilic necrotizing vasculitis involving small vessels.[87]

Papular acrodermatitis of childhood (PAC) is a cutaneous disease reported to be caused by chronic HBV, but this is unsubstantiated.[99] This disease has also been called 'Gianotti-Crosti Syndrome.'[23] It is most prevalent in the Mediterranean region. Histology reveals a superficial perivascular lymphophagocytic infiltrate with mild endothelial swelling.[20],[99] However, there are no clear histological features of vasculitis and no conclusive evidence of HBsAg deposition in the skin.[23],[99] Clinically, this disorder is characterized by nonpruritic erythematous, 2-3 mm popular eruptions in children, primarily of the face and extremities; lymphadenopathy (inguinal and axillary); and anicteric acute hepatitis found in association with HbsAg.[23],[99] Usually, the children are ages 2-6 years, rarely older than age 10 years. Anti-HBs is not detected during the dermatitis phase, but peaks 6-12 months later; hence, HBsAb has been postulated to play a role in recovery.[20] Interestingly, subtyping of the HBsAg in PAC reveals almost all patients have subtype ayw.[99]


   Arthritic manifestations Top


Arthritis following the acute prodromal infection may persist intermittently or indefinitely. However, joint destruction is very rare.[85] There is one early case report of persistent polyarthritis due to HBV infection completely resolving after 14 weeks of interferon-α therapy.[100] The resolution of arthritic symptoms paralleled HBsAg clearance. The arthralgias associated with chronic hepatitis are characteristically an asymmetrical polyarthritis with erythematous skin lesions.[86] Deposition in synovium of circulating IC's containing HBsAg-anti-HBs, immunoglobulins, complement components and HBsAg have been demonstrated in chronic HBV.[85] Additionally, Wands et al. noted that in patients with chronic HBV and arthritis, cryoprecipitates containing IgM, IgG, IgA, C3, C4 and C5 were found in the synovia containing high concentrations of HbsAg.[85] These cryoprecipitates were not found in patients with uncomplicated chronic HBV infection. Due to the lack of significant joint destruction, rarely is there demonstrable radiographic evidence to assist with the diagnosis.[30]

An association of chronic HBV with polymyalgia rheumatica has been reported,[101] but is controversial based on many discrepancies in the immunopathology.[13] Also, associations of chronic HBV with polymyositis and HLA-B27+ ankylosing spondylitis have been reported, but unconfirmed.[102],[103],[104]


   Neurologic manifestations Top


Peripheral neuropathy was described in a patient with chronic HBV.[105] Guillain-Barre syndrome has been reported to be associated with chronic HBV, but this is unconfirmed.[106]


   Conclusions Top


Several extrahepatic manifestations are associated with chronic HBV infection, many with significant morbidity and mortality. The etiology of these extrahepatic manifestations is generally believed to be immune-mediated. PAN is a rare, but serious, systemic complication of chronic HBV affecting the small- and medium-sized vessels. Interestingly, PAN is seen more frequently in North American and European patients and rarely in Asian patients. PAN ultimately involves multiple organ systems, some with devastating consequences, though the hepatic manifestations are often more mild. The optimal treatment of HBV-associated PAN is felt to include a combination of antiviral and immunosuppressive therapies, along with concomitant plasma exchange. HBV-associated glomerulonephritis (GN) occurs mainly in children, predominantly males, in HBV endemic areas of the world, but is only occasionally reported in the United States. In children, GN is usually self-limited with only rare progression to renal failure. In adults, the natural disease course of GN may be more relentless, slowly progressing to renal failure. Immunosuppressive therapy in HBV-related GN is not recommended, but antiviral therapy with α-interferon or lamivudine has shown promise. The serum-sickness like 'arthritis-dermatitis' prodrome is seen in approximately one-third of patients acquiring HBV. The joint and skin manifestations are varied, but the syndrome spontaneously resolves at the onset of clinical hepatitis with few significant sequelae. Occasionally, arthritis following the acute prodromal infection may persist; however, joint destruction is rare. The association between HBV and mixed essential cryoglobulinemia remains controversial; but a triad of purpura, arthralgias and weakness, which can progress to nephritis, pulmonary disease and generalized vasculitis, has characterized the syndrome. Finally, skin manifestations of HBV infection typically present as palpable purpura. Though papular acrodermatitis of childhood (PAC) has been reported to be caused by chronic HBV, this association remains controversial.

 
   References Top

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    Abstract
    Introduction
    Polyarteritis nodosa
    Glomerulonephritis
    Serum sickness -...
    Essential mixed ...
    Dermatologic man...
    Arthritic manife...
    Neurologic manif...
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