|Year : 2020 | Volume
| Issue : 3 | Page : 142-150
Dermatological diseases associated with Hepatitis B virus infection
Jui-Wen Yeh1, Hsing-San Yang2, Chao-Chun Yang3
1 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
3 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
|Date of Submission||17-Jan-2020|
|Date of Decision||10-Mar-2020|
|Date of Acceptance||19-Mar-2020|
|Date of Web Publication||10-Sep-2020|
Dr. Chao-Chun Yang
Department of Dermatology, National Cheng Kung University Hospital, No. 138, Sheng-Li Rd., 704 Tainan
Source of Support: None, Conflict of Interest: None
Hepatitis B virus (HBV) infection is a critical public health issue worldwide. The prompt recognition of skin diseases associated with HBV enables the earlier diagnosis of undetected HBV infection. This review article aims to provide a guide for physicians to increase awareness of possible HBV infection when encountering skin diseases. The frequencies of HBV infection were highest in telangiectasia macularis multiplex acquisita, followed by mixed cryoglobulinemia (MC), polyarteritis nodosa (PAN), and Gianotti-Crosti syndrome (GCS). Serology tests for HBV are recommended for patients with the above diseases. Lichen planus is not associated with HBV according to the most recent evidence. Chronic urticaria and porphyria cutanea tarda are associated with HBV infection although the detection rate of HBV was only 2% in these two diseases. The mechanism behind the associations between HBV and these skin disorders remains unknown and virus-associated immune-mediated processes or direct injury caused by viral replication are frequently proposed. The clinical manifestation was not discrepant between the HBV-associated skin disorder and the non-HBV-associated counterpart. The duration of HBV infection did not show any statistically significant correlations with the development of skin disorders. Antiviral medication yielded improvement in HBV-associated PAN, MC and GCS.
Keywords: Cryoglobulinemia, Gianotti-Crosti syndrome, hepatitis B virus, polyarteritis nodosa, skin diseases
|How to cite this article:|
Yeh JW, Yang HS, Yang CC. Dermatological diseases associated with Hepatitis B virus infection. Dermatol Sin 2020;38:142-50
| Introduction|| |
Hepatitis B virus (HBV) infection is one of the most critical public health issues worldwide. According to the World Health Organization, an estimated 257 million people are currently diagnosed with HBV infection. However, only 10.5% of them were aware of the infection, and <2% of them received treatment. HBV plays a crucial role in the pathogenesis of potentially life-threatening diseases, such as liver cirrhosis and hepatocellular carcinoma. In 2015, HBV infection resulted in approximately 887,000 deaths, mostly due to the complications mentioned above.
In Taiwan, according to the Ministry of Health and Welfare estimates, there are 2 million HBsAg carriers, indicating that HBV infection is a highly prevalent disease. In addition, an average of 123 confirmed indigenous cases of acute HBV infection were reported during 2015–2019 in Taiwan. Due to the initiation of the national vaccination program in 1984, the prevalence and incidence of HBV infection dropped over the years. In a recent retrospective analysis, the prevalence of chronic HBV infection in university students decreased from 9.7% to <1%, after 30 years of Taiwan's national vaccination program.
Early detection and treatment of HBV infection are crucial to avoid the development of serious complications. Furthermore, the eradication of HBV infection not only relies on vaccination but also early detection of established HBV infection of which patients are unaware.
In this article, a comprehensive review of the dermatological diseases, which are linked to HBV infection in the literature, is provided. This article aims to serve as a reference to remind physicians, especially dermatologists, to check the HBV profiles when receiving patients with specific skin diseases. The article also summarizes the specific clinical features in HBV-associated skin diseases regarding the epidemiology, pathogenesis, clinical manifestation, and therapeutic effect of anti-HBV medication. The skin manifestations which are associated with liver dysfunction in general, and are not directly related to or specific to HBV infection, are not included in this review.
| Urticaria|| |
Urticaria is an immune and vascular reaction characterized by transient pruritic, edematous and erythematous plaques of varying sizes. Urticaria is often associated with angioedema on the lips, periorbital area, extremities, and genitals.
Urticaria is classified into acute or chronic urticaria depending on whether the course of the disease is shorter or longer than 6 weeks. Diagnosis of urticaria can be made based on clinical presentation.
Association of urticaria and hepatitis B virus
Acute urticaria is the most common cutaneous manifestation associated with HBV infection. Previous studies revealed that 14.5% of HBsAg carriers had urticarial rash with a stronger predilection in females (15.6%) than in males (13.8%). Urticaria, together with fever, myalgia, and arthralgia, are the characteristics of serum sickness-like syndrome (SSLS), which can be observed in 10-20% of patients with acute HBV infection. SSLS of an HBV infection is an immune complex disease associated with type III hypersensitivity reactions. The clinical course of SSLS parallels the duration of HBV viremia, where clearance of HBV leads to resolution of the sickness. SSLS may also occur in patients with chronic HBV infection during a reactivation phase.
Chronic urticaria was thought to be associated with HBV infection in early studies. In the United States, a study of 85 patients with chronic urticaria showed that HBsAg was found in 2 (2.4%) patients, and anti-HBsAg was found in 13 (15.3%) patients, indicating that the frequency of active or past HBV infection was therefore several times greater than that reported in the general population. In a cohort study in Taiwan, HBV was significantly more common in the urticaria group than in the non-urticaria control group (2.06% vs. 1.67%). However, recent reports have shown absence of association between chronic urticaria and HBV. A retrospective study of 339 German patients with chronic urticaria revealed only 1 (0.3%) patient with active hepatitis B and 4 (1.3%) patients with previous infection. Hepatitis A, B, and C were all tested in the study, in which past hepatitis A virus infection was found in 25 patients (8.3%); no active or past hepatitis C virus (HCV) infections were detected. Another prospective multicenter questionnaire epidemiologic study in China also showed that chronic hepatitis B was less prevalent in chronic urticaria patients compared with the general Chinese population (2.7% vs. 7%). A recent systemic analysis revealed that hepatitis B was found in 0%–30% of patients with chronic urticaria (≤5% in 17 of 21 studies), as compared to 0.7%–6.2% in the normal population worldwide.
To sum up the findings above, acute urticaria can be present as a part of SSLS in HBV infection, and the association between chronic urticaria and HBV infection is so far inconclusive.
Typical urticaria is thought to be mediated by mast cells and basophils in the superficial dermis, regardless of whether it is acute or chronic. These cells activate histamine and vasodilatory mediators. Angioedema occurs when mast cells in deep dermis and subcutaneous tissue are also activated.
Infections, such as HBV, can act as a trigger to the immune reaction in urticaria although the exact pathogenesis is still unclear. In a case report of two patients with SSLS associated with acute HBV infection, deposition of HBsAg, C1q, and C3 was found in the blood vessel walls of the superficial dermis in urticarial lesions. This finding suggests that circulating immune complexes, which were induced by HBV viral antigens, triggered the activation and fragmentation of complements. One of the complement fragments, C3a, can cause the degranulation of mast cells, thus releasing histamine and vasodilatory mediators.
Clinical features and treatment of hepatitis B virus-associated urticaria
Urticaria may occur early at the prodromal stage of HBV infection or throughout the course of infection. Urticaria usually disappears by the time the patient becomes jaundiced. The cutaneous manifestations of HBV-associated acute urticaria are similar to non-HBV-associated urticaria, thus lacking a specific sign to suggest viral etiology. Two studies, with a total of 16 patients, focused on whether specific antiviral therapy of hepatitis B infection can lead to the remission of chronic spontaneous urticaria and both had negative results.,
| Polyarteritis Nodosa|| |
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that affects medium-sized arteries of multiple organ systems. Previous studies showed that 37% to 49.7% of PAN patients had skin involvement. Dermatologic manifestations in PAN include tender erythematous nodules, purpura, livedo reticularis, ulcers, and vesicular or bullous eruptions [Figure 1].
|Figure 1: Polyarteritis nodosa. A 42-year-old male patient had hepatitis B virus infection for more than 20 years and current lab test showed positive HBsAg but undetected viral load, suggesting chronic hepatitis B virus infection. Some tender infiltrating indurated cord-like nodules developed on the medial side of bilateral thighs. A skin biopsy confirmed the diagnosis of polyarteritis nodosa|
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Association of polyarteritis nodosa and hepatitis B virus
The association of hepatitis antigenemia and systemic PAN was first recognized in 1970. The French Vasculitis Study Group published retrospective research on 341 patients with PAN between 1972 and 2002, which had 115 (33.7%) cases related to HBV. In 27.8% (32 out of 115) of the PAN patients, HBV was diagnosed prior to PAN, while in 14.7% (17 out of 115) HBV was diagnosed after PAN. The presence of HBeAg and/or the detection of HBV DNA at >105 copies/ml were strongly associated with PAN and were listed as two of the positive diagnostic criteria for PAN. In another study, the frequency of HBV in PAN patients has declined gradually from 52.0% in 1970–1981 to 17.4% in 1997–2002, probably due to immunization and improvement of public health services.
The pathogenesis of idiopathic generalized PAN remains unknown, although the clinical responses to immunosuppressive therapy suggest that immunological mechanisms play an active pathogenic role. In HBV-PAN, at least two mechanisms have been proposed. First, viral replication might induce direct injury to of vessel wall, since detectable HBV RNA and DNA, HBsAg, and HBcAg have been identified in the damaged vascular endothelium in PAN patients. Second, vasculitis in PAN may result from the deposition and/or in situ formation of circulating immune complexes. These factors activate the complement cascade, which in turn attracts and activates neutrophils.
Clinical features and treatment of hepatitis B virus-associated polyarteritis nodosa
The most common initial symptoms of HBV-PAN are constitutional symptoms (74.7%), including fever, weight loss, and asthenia, followed by peripheral neuropathy (27.6%) and joint pain (27.6%). Cutaneous involvement as the initial symptom accounts for only 6.9% of HBV-PAN cases and presents itself as urticarial, bullous, or infiltrating purpuric lesions.
In a retrospective study of 348 patients diagnosed with PAN, the mean onset age of HBV-PAN was 51.7 years, with males outnumbering females (2.1:1). The onset age and sex predilection were not significantly different between HBV-PAN and non-HBV-related PAN. However, the clinical presentation of HBV-PAN and non-HBV-PAN was significantly different in the following aspects. Elevated transaminase level (aspartate aminotransferase and/or alanine aminotransferase) and weight loss were greater in HBV-PAN patients. Cutaneous manifestations, including nodules, purpura, and livedoid eruption, were less common in HBV-PAN. Patients with HBV-PAN had more severe disease compared to patients with non-HBV-related PAN. The 1, 5, and 10-year survival rates were also lower in HBV-PAN patients, in addition to the relapse rate. Multivariate analysis did not show HBV infection as being independently associated with higher mortality, and on the contrary, non-HBV-related PAN was an independent predictor of relapse with a corresponding hazard ratio of 2.27 (95% confidence interval [CI] 1.11–4.63).
The current recommendation is to treat HBV-PAN with initial administration of corticosteroids for 2 weeks to ameliorate the severe symptoms/signs of PAN. Lamivudine is initiated after 2 weeks to terminate viral replication, with the addition of plasmapheresis for removing immune complexes in severe cases. Antiviral treatment should be maintained up to 6 or 12 months, and plasmapheresis until the resolution of HBV replication or for a maximum of 2–3 months.
| Cryoglobulinemia|| |
Cryoglobulinemia refers to the presence of cryoglobulins in the serum which precipitates in cold temperature and deposits in the small blood vessels. Type II and III cryoglobulinemia, also named mixed cryoglobulinemia (MC), is associated with chronic inflammatory states including connective tissue diseases and viral infections (e.g., HBV and HCV).
MC usually manifests itself as vasculitis involving the skin, liver, kidney, musculoskeletal system and nervous system. The cutaneous manifestations of MC include palpable purpura, skin necrosis, ulcers, and acrocyanosis [Figure 2]. Other clinical manifestation includes glomerulonephritis, arthralgia, peripheral neuropathy, and myalgia.
|Figure 2: Mixed cryoglobulinemia. A 75-year-old male patient had incidental finding of occult hepatitis B virus infection during admission at nephrology ward for survey of cryglobulinemia. He had negative HBsAg but detectable hepatitis B virus viral load. Multiple palpable purpuras developed on the lower legs, dorsal feet and toes. The findings of a skin biopsy were consistent with cryoglobulinemia. Direct immunofluorescence study of the skin specimen revealed vascular staining of IgG, IgA, IgM and C3. Tests of rheumatoid factors, plasma and serum cryoproteins all showed positive results|
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Association of mixed cryoglobulinemia and hepatitis B virus
The association between HBV and cryoglobulinemia was first mentioned in 1977. Levo et al. found 12% (3 out of 25) of the serum specimens from patients with cryoglobulinemia contained HBsAg, and 48% (12 out of 25) had anti-HBs Ab. In the cryoprecipitates from blood, 74% (14 out of 19) were positive for HBsAg or its antibody. Electron microscopy on the cryoprecipitates revealed structures resembling the characteristics of HBV, such as the 20-nm and 27-nm spheres, tubules, and Dane particles.
A retrospective single-center study of cryoglobulinemia in China from 2003 to 2013 found that 36.7% (11 out of 30) of patients had HBV infection. In a more recent study of non HCV-related MC, HBV accounted for 22% (4 out of 18) of the infections causative agents. On the other hand, MC was documented in 15% of the patients with chronic HBV infection. A review paper that summarized 44 papers and 115 patients of HBV-associated skin disorders revealed that MC was the most frequently reported skin disease (41%) in chronic HBV infection.
The pathogenesis of MC in HBV patients remains unclear. It is possible that HBV virion and anti-HBV immunoglobulin are cross-linked by monoclonal rheumatoid factors and lead to formation of cryoglobulins, as in the case of HCV-related MC. On the other hand, hepatic dysfunction caused by hepatitis could decrease the clearance of circulating immune complexes and promote their deposition on vessel walls. The deposition of HBV-related immune complexes and cryoglobulins on endothelial surfaces may lead to vascular inflammation.
Clinical features and treatment of hepatitis B virus-associated mixed cryoglobulinemia
In a multicenter retrospective study of 17 patients with HBV-associated MC, the mean age was 56 years, the females outnumbered the males (59% vs. 41%) and type II cryoglobulinemia predominated (88%). Clinical presentations included purpura (100%), arthralgia (71%), peripheral neuropathy (29%), Raynaud phenomenon (18%), glomerulonephritis (18%), and leg ulcers (6%). ALT was elevated in 14 cases (82%) with a median level of 71 U/L (range: 36–114 U/L). Forty-seven percent of them had chronic hepatitis, and 29% had liver cirrhosis. Clinical manifestation of HBV-associated MC is similar to non HBV-associated MC, in which purpura is the most common symptom.
Antiviral drugs encompass an important part of the treatment of HBV-associated MC. Current studies showed effective results when using mono-therapy of antiviral drugs.,,, A French nationwide retrospective study of non HCV-related MC revealed remission was achieved in all patients with HBV who received antiviral treatment, with 33% of patients (1 out of 3) relapsing after remission. Response to entecavir treatment showed total regression of purpura, reduction of cryocrit and no detection of HBV at 12 months. Immunosuppressive therapy should be used in patients with rapidly progressing nephritis and involvement of the central nervous, digestive, and pulmonary systems.
| Lichen Planus|| |
Lichen planus (LP) is a chronic mucocutaneous inflammatory disease that may also affect nails, the scalp, and genitalia. LP is characterized by pruritic, violaceous, polygonal papules, or plaques. Associated symptoms are nail dystrophy or total nail loss in nail LP, scarring alopecia in lichen planopilaris, and erosive lesion in the mucous membrane. The estimated prevalence of cutaneous LP is <1%. For oral LP, research that included 21 clinic- and 24 population-based studies showed that the overall age-standardized estimated prevalence was 1.27% in the general population and that the disease often affects middle-aged adults, with predisposition to women.
Association of lichen planus and hepatitis B virus
In 1984, Rebora et al. found that nine of eleven patients with erosive LP had chronic active hepatitis. In the same year, a retrospective study also revealed a higher prevalence of chronic active hepatitis (11.3%) in patients with nonerosive LP. In 1990, a case–control study confirmed the risk of LP was higher in patients with a history of HBV infection (relative risk = 1.8, 95% CI = 1.0–3.1). Two years later, another study revealed that 54% of LP patients had antibodies to HBsAg.
However, recent studies do not support the association between HBV and LP. In a large case–control study, the prevalence of HBV infection in LP patients was higher than in non-LP control subjects (0.9% vs. 0.5%), but the difference was not statistically significant. Multivariate logistic regression analysis indicated that LP was not associated with hepatitis B (odds ratio 1.69, 95% CI = 0.82–3.47).
Studies focusing on the association between HBV and oral LP consistently showed negative results., For genital LP, a study in England found no association with HBsAg carrier status as well.
There were no reports addressing the mechanism of HBV-associated LP and data about the specific clinical manifestation or treatment for HBV-associated LP were also lacking. In conclusion, LP is not likely to be associated with HBV infection based on the latest knowledge. However, LP and lichenoid lesions were the most predominant cutaneous change associated with hepatitis B immunization (87.5%), although the mechanism was still unknown. To date, there are no studies about the role of antiviral treatment in HBV-associated LP.
| Gianotti-Crosti Syndrome|| |
Gianotti-Crosti syndrome (GCS) is a symmetric papular exanthem distributed on the face, buttocks, and extensor surfaces of the extremities. Systemic findings of GCS include malaise, low-grade fever, and diarrhea. Lymphadenopathy can be detected in 25% to 35% of patients, especially in the cervical, axillary, or inguinal regions. In the past, GCS was considered to be a pediatric disease, hence the name “papular acrodermatitis of childhood”. However, several case reports of GCS in adults have been published over the past decade.
Association of Gianotti-Crosti syndrome and hepatitis B virus
In 1953, Ferdinando Gianotti published his first case of GCS with speculation of a viral etiology. The first epidemic appearance of HBV-associated GCS was published in 1976, and HBsAg was detected in 88.9% (48 out of 54) of the GCS patients. In another retrospective analysis of pediatric GCS cases from 1955 to 1989, 22.4% (69 out of 308) were caused by HBV. However, the reports of HBV-associated GCS have been decreasing over the last decade, perhaps due to effective vaccination of HBV. Nowadays, the Epstein–Barr virus has become the most common cause of GCS.
Throughout the years, circulating viruses or immune complexes causing skin lesions, or triggering delayed hypersensitivity reactions have been proposed as the pathogenesis of GCS. Brandt et al. suggested the unlikeliness of direct interaction between viral antigen and immune cells, due to only rare discoveries of viral particles or antigens in the skin lesions. However, a more recent study found HBsAg deposition in the upper dermal vessels of lesion skin and perilesional skin.
Clinical features and treatment of hepatitis B virus-associated Gianotti-Crosti syndrome
Gianotti categorized GCS in to two subtypes according to presence or absence of HBsAg and claimed that the two subtypes are distinctly different, i.e., papular and non-pruritic in HBV-associated GCS versus papulovesicular and pruritic in non-HBV-associated GCS. However, further studies failed to demonstrate clinical variations between the two forms.
GCS is a self-limited disease with good prognosis. The cutaneous lesion of GCS usually fades over 10–60 days, whereas lymphadenopathy takes months to resolve. No treatment is needed in most cases, but midpotency topical corticosteroids can be applied to accelerate the blanching of skin lesions. In a case report, ribavirin was used in a child with long-lasting GCS, who showed symptomatic remission after five days. Antiviral treatment may be initiated if serum transaminases and jaundice continue to increase despite the regression of skin lesions.
| Porphyria Cutanea Tarda|| |
Porphyria cutanea tarda (PCT) is either a congenital or an acquired subtype of porphyria, characterized by the decreased activity of uroporphyrinogen decarboxylase (UROD) to synthesize heme. As a result of decreased UROD activity, porphyrins accumulate in the liver, leading to iron overload, and are readily detectable in plasma and urine. Cutaneous manifestations of PCT include bullae (85%), increased skin fragility (75%), facial hypertrichosis (63%) and hyperpigmentation (55%). Associated symptoms are photosensitivity and hepatic involvement leading to elevations in serum aminotransferase levels.
Association of porphyria cutanea tarda and hepatitis B virus
The frequencies of HBV infection in patients with PCT were vastly different over time. In 1995, a retrospective study showed detection of HBV DNA in 40% of patients. More recent studies revealed only 2%–6% of PCT patients had HBV infection., Today, researchers mostly focus on the association between PCT and HCV infection, rather than HBV infection, due to the stronger correlation and higher prevalence.
PCT can be classified into three types based on different causes. Type I, which represents acquired etiologies including HBV infection, accounts for 75%–80% of PCT cases. Types II and III are both characterized by hereditary genetic deficiencies. The pathogenesis of HBV infection leading to PCT remains to be elucidated. It is possible that HBV infection aggravates iron overload in PCT patients.
Clinical features and treatment of hepatitis B virus-associated porphyria cutanea tarda
Studies have failed to differentiate clinical manifestations of HBV-associated PCT from non-HBV-associated PCT. However, it is reported that long-term prognosis was poorer in HBV-associated PCT in terms of the development of liver cirrhosis and hepatocellular carcinoma.
Treatments of PCT include reduction of susceptibility factors in addition to repeated phlebotomy and low-dose hydroxychloroquine. To date, there are no studies about the efficacy of antiviral treatment for HBV-associated PCT.
| Telangiectasia Macularis Multiplex Acquisita|| |
Telangiectasia macularis multiplex acquisita (TMMA) is a rare skin disorder, which is exclusively reported in Asians. TMMA is characterized by multiple erythematous macules with asymptomatic telangiectasia. Common distribution of skin lesions includes the arms (100%), chest (68%), thighs (28%), and back (20%) [Figure 3]. Due to the innocuous and slowly progressive nature of TMMA, patients usually have years of disease development before coming for professional medical advice.,
|Figure 3: Telangiectasia macularis multiplex acquisita. A 52-year-old male patient had history of hepatitis B virus infection for unknown period. There were asymptomatic multiple erythematous macules with telangiectasia on the upper chest, upper back and upper arms. Some of the telangiectasias were arranged in the annular form|
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Association of telangiectasia macularis multiplex acquisita and hepatitis B virus
In a retrospective study of 25 patients with TMMA from 2002 to 2010 in Taiwan, HBV carriers were identified in 47.83% (11 out of 23) of the TMMA patients, higher than the prevalence of HBV carriers in the general population (17.3%). More recent case reports support the strong correlation of TMMA with HBV.,
Pathogenesis of hepatitis B virus-associated telangiectasia macularis multiplex acquisita
TMMA is thought to be associated with HBV infection, congenital defects, hypertension, alcohol and tobacco. The hypothesis of the pathogenic mechanism of HBV-associated TMMA awaits to be proposed.
Clinical features and treatment of hepatitis B virus-associated telangiectasia macularis multiplex acquisita
The clinical manifestations of HBV-associated and non-HBV-associated TMMA did not differ except for hypertension, which is higher in HBV-associated TMMA. Data regarding the treatment of TMMA are rare, although dye laser use to treat telangiectasia for aesthetic reason was suggested. However, no study related to this topic has been published yet.
| Corticosteroid Treatment for Hepatitis B Virus Carriers|| |
Systemic corticosteroids are frequently used to treat skin diseases which are associated with HBV infection. However, the use of immunosuppressive agents in patients with previous or chronic HBV infection poses risks for HBV reactivation. According to American Gastroenterological Association guidelines, HBsAg-positive/anti-HBc-positive patient treated with moderate-dose (10–20 mg prednisone daily or equivalent) or high-dose (>20 mg prednisone daily or equivalent) corticosteroids daily for more than 4 weeks are categorized as a high-risk group. “High risk group” was defined as having anticipated incidence of reactivation in >10% of cases. Thus, it was strongly recommended that HBV carriers should receive antiviral prophylaxis during the use of systemic corticosteroids, especially in the high-risk group as mentioned above. The antiviral drug should be maintained at least 6 months after discontinuation of systemic steroid treatment, and at least 12 months after discontinuation of B cell depleting agents such as rituximab.
| Conclusion|| |
The frequencies of HBV detected in association with relevant skin diseases are summarized in [Table 1]. The highest rate of HBV carriers was identified in TMMA, followed by MC, PAN, and GCS. Therefore, serology tests for HBV infection are strongly recommended with the above diseases [Figure 4].
|Table 1: Summary of the frequency with hepatitis B virus and responsiveness to antihepatitis B virus therapy in hepatitis B virus-associated skin diseases|
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|Figure 4: The skin diseases that warrant serology tests for hepatitis B virus infection. Patients with skin diseases, which are encircled by the red dot line in the figure, were recommended to receive hepatitis B virus tests (AN: Acanthosis nigricans; CU: Chronic urticarial; EET: Erythema elevatum diutinum; GA: Granuloma annulare; GCS: Gianotti-Crosti syndrome; LP: Lichen planus; LV: Livedoid vasculopathy; MC: Mixed cryoglobulinemia; PAN: Polyarteritis nodosa; PCT: Porphyria cutanea tarda; TMMA: Telangiectasia macularis multiplex acquisita; WM: Waldernström's macroglobulinaemia)|
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HBV infection can be categorized into four stages: immune tolerant, immune clearance, inactive carrier state, and reactivation stage. Acute urticaria, as a part of SSLS, may occur during the earlier phases of HBV infection, i.e., the immune tolerant or immune clearance stages. The other skin disorders are more likely to develop in the inactive carrier stage. Duration of the positivity of HBsAg did not show a statistically significant correlation with the development of skin disorders.
The role of HBV in the pathogenesis of HBV-associated skin disorders largely remains unknown or hypothetical. Popular hypotheses include an immune-mediated process such as the deposition of an immune complex in urticaria patients that leads to immune activation, or direct injury caused by viral replication in PAN as well as GCS patients.
Most studies failed to identify the clinical discrepancy between the HBV-associated skin disorder and the non-HBV-associated counterpart, except HBV-PAN in which cutaneous manifestations are less common and prognosis was poorer than with non-HBV-PAN. The use of anti-HBV treatment was shown to improve HBV-associated skin disorders in PAN, MC and GCS.
In conclusion, HBV infections are associated with a variety of skin disorders. Prompt recognition of HBV infection in association with these skin disorders may help with the treatment and prognosis of both conditions.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work was supported by a grant from the Ministry of Science and Technology, Taiwan (MOST 108-2628-B-006-018).
Conflicts of interest
There are no conflicts of interest.
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