Case of cryoglobulinaemia associated with chronic hepatitis B
- 1 Department of Medicine, The University of Texas Rio Grande Valley School of Medicine, Weslaco, Texas, USA
- 2 Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Correspondence to Dr Daryl T-Y Lau; dlau@bidmc.harvard.edu
Abstract
We present a case of a woman in her 50s with chronic hepatitis B (CHB) who had a longstanding history of arthralgia and swollen joints associated with severe fatigue. Investigations were consistent with a diagnosis of hepatitis B virus (HBV)-related cryoglobulinaemia. Two months after treatment with tenofovir alafenamide, an antiviral therapy for HBV, there was a significant improvement of her symptoms and undetectable serum cryoglobulins. Cryoglobulinaemia is a relatively rare extrahepatic manifestation of HBV infection and only presents in about 2%–4% of the patients with CHB. Its clinical manifestations include purpura, renal dysfunction, arthralgias and neuropathy. Since the presentation of cryoglobulinaemia in CHB can be non-specific, one needs to have a high index of suspicion to avoid delay in diagnosis and treatment.
Background
Cryoglobulins are immunoglobulins (Igs) or a mixture of Igs and complement components that undergo reversible precipitation at temperatures below 37°C. Based on the composition of cryoglobulins, cryoglobulinaemia can be classified into three types. In type I, cryoglobulins are monoclonal Igs, typically IgM and less frequently IgG or IgA; it is associated with lymphoproliferative disorders and B cell lineage malignancies such as non-Hodgkin’s lymphoma. Types II and III are mixed cryoglobulinaemia. Type II comprises polyclonal IgG and a monoclonal IgM with rheumatoid factor (RF) activity; it is usually associated with viral infection. Type III is composed of polyclonal mixed Ig including polyclonal IgM with RF; it is often related to autoimmune disorders. Types II and III can exist together and represent 70% of all cases of cryoglobulinaemia with monoclonal or polyclonal IgM associated with RF activity.1 2 For patients with type I cryoglobulinaemia, their cryocrit level is about 50%. In contrast, those with type II/III generally have less than 5% cryocrit level.3
Hepatitis C virus (HCV) accounts for >90% of the cases of mixed cryoglobulinaemia while hepatitis B virus (HBV) infection accounts for only 2%–4%.3 4 The majority of the patients with cryoglobulinaemia are asymptomatic without end organ damage. Cryoglobulinaemia syndrome should be suspected in patients presented with arthralgias, fatigue, purpura, skin ulcers, glomerulonephritis and peripheral neuropathy. Our patient experienced arthralgias and severe fatigue for many years before the diagnosis of HBV-associated cryoglobulinaemia was made.
Case presentation
A woman in her 50s presented with arthralgias involving multiple joints and severe fatigue for 8 years. She was initially diagnosed with rheumatoid arthritis (RA) and was treated with Chinese herbs without much relief. Thereafter, she was evaluated by a rheumatologist and was documented to have a positive RF, negative anti-cyclic citrullinated peptide (anti-CCP) and negative antinuclear antibody (ANA). She had no classic signs of RA and the X-ray of both hands was unremarkable. No further evaluation until her symptoms worsen years later.
Four years later, she described increased fatigue, dizziness, joint pain and swelling. She did not use non-steroidal anti-inflammatory drugs (NSAIDs) due to epigastric pain and gastritis. A brief course of prednisone (10 mg/day) was initiated, but she stopped taking it after 3 days due to nausea and aggravated fatigue. She was later noted to have asymptomatic elevation of serum aminotransferases (AST 41 U/L, ALT 33 U/L) that prompted viral hepatitis screening. It reported positive hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (Anti-HBc). Hepatitis B e antigen, anti-HCV and anti-HIV were negative.
Investigations
The patient was referred to our liver clinic for further evaluation 5 days after initiating antiviral therapy. On further inquiry, she mentioned experiencing numbness and pain of her fingers with cold exposure. She would wear gloves when taking food items from the refrigerator or touching cold surfaces. She denied having skin rash or ulceration. We ordered a cryoglobulin test and it was positive with 0.5% cryocrit. Her RF was 79 IU/mL with normal C2 and C4 levels. The fibroscan score was 3.9 kPa which was consistent with minimal hepatic fibrosis. Within 2 months of starting tenofovir alafenamide (TAF), her joint pain significantly improved. HBV DNA and cryocrit were both undetectable and serum aminotransferases normalised with ALT and AST at 11 U/L and 23 U/L, respectively (table 1).
Illustrates the changes in the HBV DNA, cryoglobulin and RF levels after starting antiviral therapy
| HBV DNA (log IU/mL) | RF (IU/mL) | Cryocrit (%) | |
| 1 month prior to HBV therapy | 4.64 | *(1:32) | |
| 5 days on TAF | 79 | 0.5 | |
| 2 months on TAF | <1 | 51 | undetectable |
| 4 months on TAF | <1 | 34 | undetectable |
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HBV, hepatitis B virus; RF, rheumatoid factor; TAF, tenofovir alafenamide.
Differential diagnosis
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Rheumatoid arthritis: it was ruled out based on the normal hand X-ray, together with negative anti-CCP and inflammatory markers.
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Extrahepatic manifestations of HBV infection especially polyarteritis nodosa (PAN). The presentation of PAN and cryoglobulinaemia overlaps. However, PAN usually presents with more acute onset of clinical symptoms in contrast to cryoglobulinaemia which has more indolent course. As PAN involves both medium and small vessels, patients with PAN usually present with symptoms of gastrointestinal tract and renal involvement such as abdominal pain and haematuria. None of these symptoms were present in our patient. Moreover, the elevated cryocrit pointed towards cryoglobulinaemia rather than PAN. Finally, PAN can be differentiated from cryoglobulinaemic vasculitis confidently either by biopsy of blood vessels revealing involvement of medium size arteries or by demonstration of microaneurysms and arterial stenosis on imaging or angiogram.
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Hypothyroidism should be considered in the differential diagnosis in female patient in her 40s and 50s who presents with fatigue, joint pain and arthralgias. It was ruled out as thyroid stimulating hormone, triiodothyronine and thyroxine were normal in this case.
Outcome and follow-up
Patient returned 4 months later for follow-up. Her repeat cryocrit and HBV DNA remained undetectable with further reduction of RF to 34 IU/mL on continuous antiviral therapy for chronic hepatitis B (CHB) (table 1).
Discussion
Extrahepatic manifestations occur in about 10%–20% of patients with CHB. These manifestations can also be seen in acute HBV infection.3 Many of the extrahepatic manifestations are viral antigen-driven and associated with immune complex deposition. These complexes often deposit in specific sites of the body including the skin, kidney and small/medium arteries causing vasculitis. Vasculitides associated with HBV can be divided into three categories, namely, PAN, cryoglobulinaemic vasculitis and leukocytoclastic vasculitis. PAN, which is associated with small and medium sized vessels, usually presents with fatigue, weight loss, weakness, fever and arthralgias. HBV-related leucocytoclastic vasculitis is very rare and is mostly associated with inflammation of very small vessel and capillaries. In contrast, cryoglobulinaemic vasculitis is limited to small vessels. It occurs in about 2%–4% of patients with HBV infection and can present with a broad range of symptoms such as arthralgia, purpura, skin ulcers, glomerulonephritis and peripheral neuropathy. Renal manifestations occur in 3%–5% of the CHB patients and are due to renal vasculitis and glomerulonephritis. Dermatological manifestations including juvenile popular acrodermatitis, acute urticarial and lichen planus; haematological manifestations such as B cell non-Hodgkin’s lymphoma and diffuse large B cell lymphoma; neurological manifestations, for example, Guillain-Barré syndrome; and ocular findings which commonly present with uveitis have also been described to be associated with HBV.5–8 In addition, serum sickness-like syndrome can also occur in 10%–20% of patients with acute HBV infection. Serum sickness-like syndrome usually presents with the symptoms of fever, erythematous skin rash, myalgia, arthralgias, malaise and fatigue. These symptoms usually resolve after recovery from acute hepatitis B.5
This patient presented with longstanding arthralgias and severe fatigue. She was initially thought to have RA due to the positive RF. RA was subsequently ruled out by the normal hand X-ray, together with negative anti-CCP and inflammatory markers. Due to worsening of her symptoms, she was started on prednisone. Since prednisone can lead to HBV reactivation, it is important to perform HBV screening prior to initiating prednisone especially in patients from HBV endemic regions. This patient was noted to have mildly elevated serum aminotransferases that prompted the viral hepatitis testing. She only took prednisone for 3 days so it remains debatable whether the abnormal liver tests were secondary to prednisone use in this case. She was subsequently started on TAF. According to the American Association for the Study of Liver Diseases (AASLD), antiviral therapy is recommended for HBeAg negative patients with HBV DNA levels persistently over 2000 IU/mL and ALT greater than two times upper limit of normal.9 However, for patients with CHB and significant extrahepatic manifestations, antiviral therapy should be considered even if their HBV DNA and ALT levels are lower than the standard treatment recommendation.9
In addition to fatigue and arthralgias, the patient also experienced symptoms consistent with Raynaud’s phenomenon. This provided clues to the possible diagnosis of cryoglobulinaemia. The improvement of her symptoms after HBV DNA suppression and reduction of RF lends further support to the diagnosis of HBV-related cryoglobulinaemia even though the level of detectable cryocrit was relatively low.
Compared with HCV, cryoglobulinaemia are relatively uncommon among patients with chronic HBV infection. In a large study from France, serum samples of 13 439 patients were analysed for the presence of cryoglobulins. 1675 samples (12.5%) which tested positive for cryoglobulins were included in the study. Mixed cryoglobulinaemia were found in 1520 (90.7%) of the patients and 155 (9.3%) had type I cryoglobulins. Among the 1675 samples tested positive for cryoglobulins, 543 and 648 were randomly evaluated for HBV and HCV status, respectively. HCV was identified in 321 of 648 (49.5%) of the cases whereas only 21 of the 543 (3.9%) cases were associated with HBV. All the HBV-positive cryoglobulins-positive and HCV-positive cryoglobulin-positive patients had mixed cryoglobulins.3
In another study from Italy, 231 patients with mixed cryoglobulinaemia were studied. About 168 were evaluated for the presence of HCV and HBV. HCV was identified in 155 (92%), whereas HBV was only found in 3 (1.8%) of the cohort.4 Both type II and type III mixed cryoglobulinaemia have been described among CHB patients in the available reports.10 11 A small study from Italy noted 15 out of 17 (88%) patients with HBV-related cryoglobulinaemia had type II cryoglobulins.10 In contrast, another small study with 12 patients, type III mixed cryoglobulinaemia in 9 patients was more common than type II present in 3 patients.11
Symptoms and signs such as arthralgia, Raynaud’s phenomenon, skin purpura, livedo reticularis, acrocyanosis, cutaneous ischaemia and peripheral neuropathy should trigger the evaluation of cryoglobulin especially in patients with viral hepatitis or autoimmune hepatitis. In addition, patients with unexplained increased RF activity and hypocomplementaemia should also be tested for cryoglobulins. A quantifiable amount of cryocrit in the serum is the hallmark of cryoglobulinaemia.
The primary therapeutic goal for this patient was to improve her severe arthralgias and fatigue that had a significant impact on the quality of her life. There is strong evidence that HBV suppression by antiviral agents such as nucleos(t)ide analogues (NA) can reduce the cryoglobulin levels and alleviate the clinical manifestations of HBV-associated cryoglobulinaemia.1 12–14 Among those with severe cryoglobulinaemic vasculitis, plasma exchange with high dose of corticosteroids may be necessary in addition to NA. Rituximab has also be used for refractory, severe cases. Since both high dose prednisone and Rituximab therapy can lead to fulminant hepatitis B reactivation, it is important to use NA concurrently to suppress HBV DNA and to monitor the liver condition closely.15 16 Fortunately, our patient experienced significant improvement of her symptoms coincided with the undetectable cryocrit and HBV DNA.
This case emphasises the importance to alert to the possibility of the extrahepatic manifestation of HBV such as mixed cryoglobulinaemia. Any atypical presentation should be further explored with detailed clinical history and additional evaluations. This case also emphasises the importance to screen for HBV before initiating immunosuppressive therapy. Usage of such agents including prednisone should be cautiously considered among patients with CHB. Prophylactic antiviral therapy may be necessary to prevent HBV reactivation.9
Learning points
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Mixed cryoglobulinaemia is most commonly associated with hepatitis C virus (HCV) infection; however, hepatitis B virus (HBV)-related cryoglobulinaemia should be considered when patients present with non-specific extrahepatic symptoms.
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For both HBV and HCV-associated cryoglobulinaemia, antiviral therapy usually leads to disease remission but non-response and relapse are possible especially among those with severe vasculitis.
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Severe HBV reactivation can occur with immunosuppressive therapy. HBV screening and prophylactic antiviral therapy need to be considered.
Ethics statements
Patient consent for publication
Footnotes
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Contributors DT-YL provided the concept and direction of writing the case report, the learning points and editing of the final manuscript; HK and KJCR reviewed the literature and wrote the first draft of the manuscript. MJA and HK contributed to the addition of literature, revision and edition of the final manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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