Clinico-biological Characteristics and Treatment of Hepatitis B Virus-Related Mixed Cryoglobulinemia
Cryoglobulinemia is a condition characterized by the presence of cryoglobulins in the serum, which precipitate at temperatures below 37°C and redissolve upon rewarming. Cryoglobulins are classified into three types: Type I, which consists of monoclonal IgG or IgM, and rarely IgA or free immunoglobulin (Ig) light chains; Type II, which is composed of monoclonal IgM with rheumatoid factor (RF) activity and polyclonal IgG; and Type III, which is made up of polyclonal IgM with RF activity and polyclonal IgG. Types II and III are collectively referred to as mixed cryoglobulinemia (MC). MC is often associated with various infectious diseases, including hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. The clinical presentation of MC is primarily characterized by cryoglobulinemic vasculitis, which may include symptoms such as fatigue, purpura, arthralgia, myalgia, peripheral neuropathy, and severe organ damage, such as glomerulonephritis. However, involvement of the gastrointestinal tract and heart is rare, and neurological, ocular, and rhino-otological symptoms of hyperviscosity syndrome are seldom observed in MC.
This article presents a case of HBV-related MC and reviews 41 additional cases from the literature to elucidate the clinico-biological characteristics and treatment of this condition. The patient, a 62-year-old man, presented with edema and purpura over the lower extremities, along with impaired renal function. Laboratory tests revealed low albumin levels (34 g/L), elevated creatinine (199.0 mmol/L), reduced complement C3 (35.60 mg/dL) and C4 (3.27 mg/dL), and a positive RF (128 IU/mL). The patient also had a 24-hour urine protein of 0.56 g with a urine volume of 200 mL. Serological studies confirmed the presence of HBV surface antigen (HBsAg), HBV envelope antibody, and HBV core antibody, while HBV DNA was not detected in the serum. Immunofixation electrophoresis identified a monoclonal IgM-kappa component in the serum and urine. Renal biopsy results indicated membranoproliferative glomerulonephritis, with hyaline thrombi in the capillary lumen and deposits of IgA, IgG, IgM, C3, and C4 on the capillary walls. Electron microscopy revealed basement membrane reduplication and organized subendothelial microtubular substructure deposits, consistent with HBV-related cryoglobulinemic glomerulonephritis. The serum cryoglobulin test was positive, with a cryoglobulin content of 2609 mg/mL, and the cryoglobulin was characterized as monoclonal IgM kappa-polyclonal IgG. The final diagnosis was type II cryoglobulinemia, HBV-related cryoglobulinemic glomerulonephritis, and rapidly progressive glomerulonephritis.
The patient was treated with prednisone, entecavir, fresh plasma transfusion (750 mL), plasma exchange (PE) (three sessions), and intravenous cyclophosphamide (CYC) (0.8 g). After 10 days, the purpura regressed, and creatinine levels decreased. However, due to financial constraints, the patient did not receive further CYC or PE therapy. Instead, he continued treatment with prednisone, entecavir, and hemodialysis twice a week at a local hospital but died six months later.
A comprehensive review of 41 HBV-related MC cases from the literature was conducted using PubMed, Embase, Web of Science, cnki.net, and the Wanfang Database. The review included cases up to September 10, 2020. The demographic information, extrahepatic clinical manifestations, laboratory test data, treatment, and outcomes were collected and analyzed. The mean age of the 42 patients (including the present case) was 53 ± 14 years, with 47.6% being male and 52.4% female. The most common extrahepatic clinical manifestations were cutaneous lesions (78.6%), kidney involvement (54.8%), and peripheral neuropathy (35.7%). Among the 34 patients tested for cryoglobulin type, 61.8% had Type II, and 38.2% had Type III. Low C3 levels (<80 mg/dL) were observed in 60.7% of patients, while 87.1% had low C4 levels (<10 mg/dL). RF was positive in 92.6% of patients. The median serum HBV DNA level was 5.0 × 10^4 U/mL, although 13.9% of patients tested negative for HBV DNA.
Treatment strategies for HBV-related MC included antiviral therapy, corticosteroids (CS), immunosuppressive agents (IS), and PE. Overall, 85.7% of patients received antiviral therapy, with entecavir (40.5%) and lamivudine (26.2%) being the most commonly used drugs. CS were administered to 52.4% of patients, and IS, including CYC, mycophenolic acid, and rituximab (RTX), were prescribed to 31.0% of patients. PE was performed in 21.4% of cases. After the first stage of therapy, 35.7% of patients achieved disease remission. However, 64.3% had refractory or relapsing disease, and seven patients entered remission after the second stage of therapy. Among these, four patients had their anti-HBV drugs adjusted, and two received RTX. One patient had their anti-HBV drugs changed and received four RTX infusions, followed by mycophenolic acid for maintenance therapy. Overall, 28.6% of patients achieved remission with anti-HBV drugs alone, while 19.0% required a combination of anti-HBV drugs, CS, IS, and PE. At the end of follow-up, 52.4% of patients were in remission, 47.6% had refractory disease, and five patients had died.
The prevalence of HBV-related MC is unclear, and geographical differences may exist in the association between cryoglobulinemia and HBV. Chronic antigen stimulation following HBV infection reduces the activation threshold and increases the proliferation of B-lymphocytes, leading to the expansion of a B-cell clone that produces antibodies with RF activity. These antibodies form immune complexes, activate complements, and induce vasculitis. The most common symptoms of HBV-related MC include purpura, kidney involvement, and peripheral neuropathy. Severe or life-threatening manifestations, such as cutaneous ulcers, progressive motor neuropathy, rapid renal failure, nephrotic syndrome, recurrent severe abdominal pain, and acute cerebrovascular or cardiovascular events, have also been reported.
The treatment of HBV-related MC focuses on suppressing HBV replication and eliminating specific B-cell clonalities. Anti-HBV drugs form the basis of treatment, and mild to moderate cases can often be managed with nucleot(s)ide analogues. For severe cases, high-dose pulsed glucocorticoids combined with PE may be used as first-line treatment, and RTX-based therapies should be considered for patients with persistent life-threatening manifestations. In this study, 20 patients had refractory disease, including five deaths, indicating that HBV-related MC can have a poor prognosis, particularly in patients presenting with severe symptoms. Further multicenter studies are needed to comprehensively investigate the outcomes of HBV-related MC and optimize treatment strategies.
doi.org/10.1097/CM9.0000000000001714
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